Inhibitors of papilloma virus

ABSTRACT

The use of a compound of formula (II):  
                 
 
or its enantiomers or diastereoisomers thereof, or salts or pharmaceutically-acceptable esters thereof, in the treatment or prevention of a papilloma virus infection, particularly human papilloma virus in a mammal, wherein R 11 ; X 4 ; X 5 ; X 6 ; R 13 ; R 14 ; W; Z; Y; T; and R 18  are defined herein. 
The present invention also provides novel compounds, pharmaceutical compositions and methods for using these compounds and compositions in the treatment or prevention of papilloma virus infection. More particularly, the present invention provides compounds, compositions and methods for inhibiting papilloma virus DNA replication by interfering with the E1-E2 protein-protein interaction essential for viral DNA replication.

FIELD OF THE INVENTION

The present invention relates to compounds, compositions and methods forthe treatment or prevention of papilloma virus (PV) infection,particularly human papilloma virus (HPV). In particular, the presentinvention provides novel compounds, pharmaceutical compositionscontaining such compounds and methods for using these compounds in thetreatment or prevention of papilloma virus infection. More particularly,the present invention provides compounds, compositions and methods forinhibiting papilloma virus DNA replication by interfering with the E1-E2protein-protein interaction during initiation of viral DNA replication.

BACKGROUND OF THE INVENTION

Papillomaviruses are non-enveloped DNA viruses that inducehyperproliferative lesions of the epithelia. The papillomaviruses arewidespread in nature and have been identified in higher vertebrates.Viruses have been characterized, amongst others, from humans, cattle,rabbits, horses, and dogs. The first papillomavirus was described in1933 as cottontail rabbit papillomavirus (CRPV). Since then, thecottontail rabbit as well as bovine papillomavirus type 1 (BPV-1) haveserved as experimental prototypes for studies on papillomaviruses. Mostanimal papillomaviruses are associated with purely epithelialproliferative lesions, and most lesions in animals are cutaneous. In thehuman, there are more than 75 types of papillomavirus that have beenidentified and they have been catalogued by site of infection: cutaneousepithelium and mucosal epithelium (oral and genital mucosa). Thecutaneous-related diseases include flat warts, plantar warts, etc. Themucosal-related diseases include laryngeal papillomas and anogenitaldiseases such as cervical carcinomas.

There are more than 25 HPV types that are implicated in anogenitaldiseases, these are grouped into “low risk” and “high risk” types. Thelow risk types include HPV type 6 and type 11, and induce mostly benignlesions such as condyloma acuminata (genital warts) and low gradesquamous intraepithelial lesions (SIL). In the United States, 1% of thesexually active population has genital warts of which 90% is attributedto HPV-6 and HPV-11.

The high risk types are associated with high grade SIL, cervical andanal cancers and include most frequently HPV types 16, 18, 31, 33, 35,45, 52, and 58. The progression from low-grade SIL to high-grade SIL ismuch more frequent for lesions that contain high risk HPV-16 and 18 ascompared to those that contain low risk HPV types. In addition, onlyfour HPV types are detected frequently in cervical cancer (types 16, 18,31 and 45). About 500,000 new cases of invasive cancer of the cervix arediagnosed annually worldwide.

Treatments for genital warts include physical removal such ascryotherapy, CO₂ laser, electrosurgery, or surgical excision. Cytotoxicagents may also be used such as trichloroacetic acid (TCA), podophyllinor podofilox. Immunomodulatory therapy is also available such asinterferon or imiquimod. These treatments are not completely effectivein eliminating all viral particles and there is either a high costincurred or uncomfortable side effects related thereto. In fact, thereare currently no commercially available effective antiviral treatmentsfor HPV infection since recurrent warts are common with all currenttherapies.

The ineffectiveness of the current methods to treat HPV infections hasdemonstrated the need to identify new means to control or eliminate suchinfections. In recent years, efforts have been directed towards findingantiviral compounds, and especially compounds capable of interferingwith viral replication at the onset of infection.

The life cycle of PV is closely coupled to keratinocyte differentiation.Infection is believed to occur at a site of tissue disruption in thebasal epithelium. Unlike normal cells, the cellular DNA replicationmachinery is maintained as the cell undergoes vertical differentiation.As the infected cells undergo progressive differentiation the viralgenome copy number and viral gene expression in turn increase, with theeventual late gene expression and virion assembly in terminallydifferentiated keratinocytes and the release of viral particles.

The coding strands for each of the papillomaviruses containapproximately ten designated translational open reading frames (ORFs)that have been classified as either early ORFs or late ORFs based ontheir location in the genome. E1 to E8 are expressed early in the viralreplication cycle, and two late genes (L1 and L2) encode the major andminor capsid proteins respectively. The E1 and E2 gene products functionin viral DNA replication, whereas E5, E6 and E7 are expressed inconnection with host cell proliferation. The L1 and L2 gene products areinvolved in virion structure. The function of the E3 and E8 geneproducts is uncertain at present.

Studies of HPV have shown that proteins E1 and E2 are the only two viralproteins that are necessary for viral DNA replication in vitro and invivo, in addition to the host DNA replication machinery. Thisrequirement is similar to that of bovine papillomavirus type 1 (BPV-1).Indeed, there is a high degree of similarity between E1 and E2 proteinsand the ori-sequences of all papillomaviruses (PV) regardless of theviral species and type. Evidence emanating from studies of BPV-1 haveshown that E1 possesses ATPase and helicase activities that are requiredin viral DNA replication.

The E2 protein is a transcriptional activator that binds to E1 proteinand forms a complex that binds specifically to the ori sequence (Mohr etal., 1990, Science 250:1694-1699), an interaction that is essential forviral DNA replication. It is believed that E2 enhances binding of E1 tothe BPV origin of replication (Seo et al., 1993b, Proc. Natl. Acad.Sci., 90:2865-2869). In HPV, Liu et al. suggested that E2 stabilizes E1binding to the ori (1995, J. Biol. Chem., 270(45):27283-27291).

To thwart this disease, a chemical entity that would interfere withviral DNA replication is therefore desirable, and the development of newand specific anti-PV, particularly anti-HPV, treatments remains a highpriority.

WO 02/50082 published on Jun. 27, 2002 discloses novel indanedionederivatives, pharmaceutical compositions containing such derivatives andmethods for using these compounds in the treatment of papilloma virusinfection.

WO 01/07027 published on Feb. 1, 2001 to Vertex PharmaceuticalsIncorporated discloses pyrimidine-based inhibitors and analogs thereoffor use in inhibiting viral helicases, including viral helicases offlaviviruses, poxviruses and papova viruses.

WO 99/55663 published on Nov. 4, 1999 to Vertex PharmaceuticalsIncorporated discloses substituted aryl compounds and derivativesthereof as inhibitors of inosine-5′-monophosphate dehydrogenase enzymeactivity which are useful for mediating IMDH mediated processes,including human papilloma virus replication.

None of the prior art teaches compounds of the present invention asinhibitors of papilloma viral DNA replication.

Structures related to the compounds of the present invention aredescribed in the following patent documents: WO 97/45400, WO 98/47879,and WO 00/24707 of Neurosearch; WO 00/71508; WO 00/71507; WO 00/71509and WO 00/71493 of Cor Therapeutics; WO 97/49286, WO 00/76501, and WO00/69435 of SmithKline Beecham; EP 0 974 576 of Mitsui Chemicals; WO97/24328 and WO 01/02350 of Bayer AG; WO 94/06280 of the University ofCalifornia; WO 95/11880 of Merck Sharpe & Dohme; and FR 2 763 590 ofSynthelabo; U.S. Pat. No. 5,312,924, U.S. Pat. No. 5,216,167; GB 2 124220 and GB 2 090 834 of Dr. Karl Thomae; U.S. Pat. No. 4,943,315, WO01/90079 and GB 2 289 893 of BASF AG; JP 09 087237 of Kyowa Hakko KogyaCo.; CA 2,191,757 of Hoechst Schering AgrEvo; EP 0 656 349 and EP 0 588655 of Ono Pharmaceutical; and EP 0 528 586 of Merck & Co. None of thesereferences teach that such related compounds can be useful in thetreatment or prevention of papilloma virus infection.

The present invention therefore provides novel compounds, compositionsand methods that inhibit papilloma viral replication. More particularly,the compounds and composition of the present invention interfere withthe E1-E2 protein-protein interaction during the viral replicationcycle.

SUMMARY OF THE INVENTION

In a first aspect, the invention provides a compound of formula (I) orits enantiomers or diastereoisomers thereof:

wherein R¹ is H, (C₁₋₆)alkyl, halo, (C₁₋₆)haloalkyl; (C₁₋₆)alkoxy,(C₁₋₆)alkylthio, amino, (C₁₋₆)alkylamino, di((C₁₋₆)alkyl)amino,(C₃₋₇)cycloalkyl, phenyl, or 5- or 6-membered heterocycle;

-   X₁ is CR² or N;-   one or both free positions on the phenyl ring may be substituted    with R² and each R² is independently selected from: H, (C₁₋₆)alkyl,    halo, (C₁₋₆)haloalkyl, (C₁₋₆)alkoxy, (C₁₋₆)alkylthio, amino,    (C₁₋₆)alkylamino and di((C₁₋₆)alkyl)amino;-   A is (C₃₋₇)cycloalkyl, aryl or heterocycle, each of which being    optionally substituted with one or more substituents independently    selected from:    -   (C₁₋₆)alkyl, halo, (C₁₋₆)haloalkyl, (C₁₋₆)alkoxy,        (C₁₋₆)alkylthio, amino, (C₁₋₆)alkylamino, or        di((C₁₋₆)alkyl)amino, aryl, O-aryl, S-aryl, NH-aryl,        (C₁₋₆)alkyl-aryl, heteroaryl, O-heteroaryl, S-heteroaryl,        NH-heteroaryl and (C₁₋₆)alkyl-heteroaryl;-   or A is NHR³ or N(R³)₂ wherein    -   each R³ is independently selected from H, (C₁₋₆)alkyl,        (C₃₋₇)cycloalkyl, aryl and heteroaryl;-   R⁴ is (C₁₋₆)alkyl, (C₃₋₇)cycloalkyl, aryl, heterocycle,    (C₁₋₆)alkyl-aryl or (C₁₋₆)alkyl-heterocycle, each of which being    optionally substituted with one or more substituents independently    selected from:    -   (C₁₋₆)alkyl, halo, (C₁₋₆)haloalkyl, (C₁₋₆)alkylthio, amino,        (C₁₋₆)alkylamino, di((C₁₋₆)alkyl)amino, aryl, heteroaryl,        (C₁₋₆)alkyl-aryl, (C₁₋₆)alkyl-heteroaryl, and (C₁₋₆)alkoxy,        wherein said (C₁₋₆)alkoxy is optionally substituted with aryl or        heteroaryl;-   or R⁴ is phenyl fused with a saturated or unsaturated 4- to    6-membered ring optionally containing one to three heteroatoms    independently selected from N, O, and S;-   Z is O or S;-   Y is CH₂, NH or O;-   B is selected from:-    wherein R⁵ is H, (C₁₋₆)alkyl, (C₃₋₇)cycloalkyl, halo,    (C₁₋₆)haloalkyl, (C₁₋₆)alkoxy, (C₁₋₆)alkylthio, amino,    (C₁₋₆)alkylamino, di((C₁₋₆)alkyl)amino, hydroxyl or sulfhydryl;-   X₂ is CR⁷ or N;-   R⁶ and R⁷ are independently H, (C₁₋₆)alkyl, halo, (C₁₋₆)haloalkyl,    (C₁₋₆)alkoxy, (C₁₋₆)alkylthio, amino, (C₁₋₆)alkylamino,    di((C₁₋₆)alkyl)amino, hydroxyl or sulfhydryl;-   or, when X₂ is CR⁷, R⁶ and R⁷ are optionally bonded together to form    a saturated or unsaturated 5- or 6-membered ring optionally    containing one or two heteroatoms independently selected from S, O    and N;-   X₃ is O, S or NR⁸, wherein R⁸ is H or (C₁₋₆)alkyl; and-   R^(c) is COOH, CONHR⁹, SO₂NHR⁹, CONHSO₂R⁹, CONHSO₂NHR⁹, triazolyl or    tetrazolyl,    -   wherein R⁹ is H, (C₁₋₆)alkyl, (C₃₋₆)cycloalkyl or phenyl;-   provided that R⁵ and R⁶ cannot both together be H and when R⁵ or R⁶    is H, then R¹ is not H, and provided that when Y is NH, R⁶ cannot be    hydroxyl or sulfhydryl;    or a pharmaceutically-acceptable salt or ester thereof.

Included within the scope of this invention are compounds of the formula(I) as described hereinbefore, to which at least one of a “detectablelabel”, an “affinity tag” or a “photoreactive group” is linked.

In a second aspect, the invention provides the use of a compound offormula (I) above in the manufacture of a medicament for the treatmentor prevention of papilloma virus infection in a mammal.

In a third aspect, the invention provides the use of a compound offormula (II) or its enantiomers or diastereoisomers thereof, in themanufacture of a medicament for the treatment or prevention of apapilloma virus infection in a mammal:

wherein R¹¹ is H, (C₁₋₆)alkyl, halo, (C₁₋₆)haloalkyl, (C₁₋₆)alkoxy,(C₁₋₆)alkylthio, amino, (C₁₋₆)alkylamino, di((C₁₋₆)alkyl)amino,(C₃₋₇)cycloalkyl, phenyl, or 5- or 6-membered heterocycle;

-   X₄, X₅ and X₆ are independently chosen from CR¹² and N, wherein    -   each R¹² is independently selected from: H, (C₁₋₆)alkyl,        (C₁₋₆)alkoxy, halo, (C₁₋₆)alkylthio, (C₁₋₆)haloalkyl, amino,        (C₁₋₆)alkylamino and di((C₁₋₆)alkyl)amino;-   R¹³ is (C₁₋₆)alkyl, (C₃₋₇)cycloalkyl, aryl, or heterocycle, said    (C₁₋₆)alkyl, (C₃₋₇)cycloalkyl, aryl and heterocycle being optionally    substituted with R¹⁵ wherein    -   R¹⁵ is H, (C₁₋₆)alkyl, (C₃₋₇)cycloalkyl, halo, (C₁₋₆)haloalkyl,        (C₁₋₆)alkoxy, (C₁₋₆)alkylthio, amino, (C₁₋₆)alkylamino, or        di((C₁₋₆)alkyl)amino, aryl, O-aryl, S-aryl, NH-aryl,        (C₁₋₆)alkyl-aryl, heteroaryl, O-heteroaryl, S-heteroaryl,        NH-heteroaryl or (C₁₋₆)alkyl-heteroaryl;-   or R¹³ is OR¹⁶, SR¹⁶, NHR¹⁶ or N(R¹⁶)₂ wherein    -   R¹⁶ is independently selected in each instance from: H,        (C₁₋₆)alkyl, (C₃₋₇)cycloalkyl, aryl and heteroaryl; and-   R¹⁴ is H, (C₁₋₆)alkyl, (C₃₋₇)cycloalkyl, aryl, heterocycle,    (C₁₋₆)alkyl-aryl or (C₁₋₆)alkyl-heterocycle, wherein said    (C₁₋₆)alkyl, (C₃₋₇)cycloalkyl, aryl, heterocycle, (C₁₋₆)alkyl-aryl    or (C₁₋₆)alkyl-heterocycle are optionally substituted with one or    more substituents independently selected from:    -   (C₁₋₆)alkyl, halo, (C₁₋₆)haloalkyl, (C₁₋₆)alkylthio, amino,        (C₁₋₆)alkylamino, di((C₁₋₆)alkyl)amino, aryl, heteroaryl,        (C₁₋₆)alkyl-aryl, (C₁₋₆)alkyl-heteroaryl, and (C₁₋₆)alkoxy,        wherein said (C₁₋₆)alkoxy is optionally substituted with aryl or        heteroaryl;-   or R¹⁴ is phenyl fused with a saturated or unsaturated 4- to    6-membered ring optionally containing one to four heteroatoms    independently selected from N, O, and S;-   or R¹⁴ is CH₂COOR¹⁷ or CH₂CONHR¹⁷, wherein    -   R¹⁷ is (C₁₋₆)alkyl, (C₃₋₇)cycloalkyl, aryl or heterocycle, said        (C₁₋₆)alkyl, (C₃₋₇)cycloalkyl, aryl and heterocycle being        optionally further substituted with:        -   aryl or heteroaryl, both being optionally substituted with            one to four R¹¹;-   W is NH or CH₂;-   Z is O or S;-   Y is CH₂, NH or O;-   T is aryl, or heteroaryl, said aryl and heteroaryl being optionally    substituted with:    -   one to three R¹¹, hydroxyl or sulfhydryl; and-   R¹⁸ is COOH, COOR¹⁹, CONHR¹⁹, SO₂NHR¹⁹, CONHSO₂R¹⁹, CONHSO₂NHR¹⁹,    triazolyl or tetrazolyl; wherein    -   R¹⁹ is H, (C₁₋₆)alkyl, (C₃₋₆)cycloalkyl or phenyl;        or a pharmaceutically acceptable salt or ester thereof.

In a preferred embodiment, the papilloma virus is a human papillomavirus. In a more preferred embodiment, the human papilloma viruscomprises a low risk type human papilloma virus, preferably type 6 ortype 11 human papilloma virus.

In a fourth aspect, the invention provides a pharmaceutical compositioncomprising a therapeutically effective and acceptable amount of acompound of formula (I) in association with at least onepharmaceutically-acceptable carrier.

In a fifth aspect, the invention provides a pharmaceutical compositionfor use in the treatment or prevention of papilloma virus infection,wherein the composition comprises a therapeutically effective andacceptable amount of a compound of formula (I) or formula (II), inassociation with at least one pharmaceutically-acceptable carrier.

In a sixth aspect, the invention provides an anti-papilloma viruspharmaceutical composition comprising an anti-papilloma virusvirally-effective amount of a compound of formula (I), or a compound offormula (II), in association with at least onepharmaceutically-acceptable carrier.

In a seventh aspect, the invention provides a use of a compound offormula (I) or a compound of formula (II), to inhibit the replication ofa papilloma virus.

In an eighth aspect, the invention provides a use of a compound offormula (I) or a compound of formula (II), in the treatment orprevention of a papilloma virus infection in a mammal.

In a ninth aspect, the invention provides a use of a compound of formula(I) or formula (II) for binding to the E2 transcriptional activationdomain of the human papilloma virus E2 protein to inhibit binding of theE2 protein to the human papilloma virus E1 protein, to inhibit viral DNAreplication in a mammal infected with a human papilloma virus.

In a tenth aspect, the invention provides a use of a compound of formula(I) or formula (II) for inhibiting the human papilloma virus E1-E2protein-protein interaction to inhibit papilloma virus viral DNAreplication in a mammal infected with the virus.

In an eleventh aspect, the invention provides a method of treating orpreventing a papilloma virus infection in a mammal comprisingadministering to the mammal an anti-papilloma virus virally-effectiveand acceptable amount of a compound of formula (I) or formula (II), or acomposition containing such a compound.

In a twelfth aspect, the invention provides a method of inhibitingreplication of a papilloma virus comprising exposing the virus to ananti-papilloma virus virally-effective and acceptable amount of acompound of formula (I) or a compound of formula (II), therebyinhibiting the human papilloma virus E1-E2 protein-protein interaction.

In a thirteenth aspect, the invention provides a method of inhibitingreplication of a papilloma virus comprising exposing virally-infectedcells to a anti-papilloma virus virally-effective and acceptable amountof at least one of a compound of formula (I) and a compound of formula(II).

In a fourteenth aspect, the invention provides a packaged pharmaceuticalcomprising a pharmaceutical composition containing a compound of formula(I) or of formula (II) and directions identifying an administrationregimen.

In a fifteenth aspect, the invention provides a packaged pharmaceuticalfor use for the treatment or prevention of papilloma virus infection ina mammal, wherein the packaged pharmaceutical comprises a pharmaceuticalcomposition containing a compound of formula (I) or formula (II) anddirections identifying an administration regimen.

In a sixteenth aspect, the invention provides an article of manufacturecomprising packaging material contained within which is a compositioneffective to inhibit a papilloma virus and the packaging materialcomprises a label which indicates that the composition can be used totreat or prevent infection by a papilloma virus, wherein saidcomposition includes a compound of formula (I) or a compound of formula(II).

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

Definitions

Unless defined otherwise, the scientific and technological terms andnomenclature used herein have the same meaning as commonly understood bya person skilled in the art to which this invention pertains but shouldnot be interpreted as limiting the scope of the present invention.

The term “eutomer” as used herein means the enantiomer, from a pair ofenantiomers, that is more active i.e. has the highest biologicalpotency.

The term “distomer” as used herein means the enantiomer, from a pair ofenantiomers, that is less active or has no potency.

The term “halo” as used herein means a halogen radical selected frombromo, chloro, fluoro or iodo.

The term “hydroxyl” as used herein means an —OH radical.

The term “sulfhydryl” as used herein means a —SH radical.

The term “(C_(1-n))alkyl” as used herein, either alone or in combinationwith another radical, means straight or branched-chain alkyl radicalscontaining from one to n carbon atoms and includes, but is not limitedto, methyl, ethyl, propyl, butyl, hexyl, 1-methylethyl, 1-methylpropyl,2-methylpropyl and 1,1-dimethylethyl.

The term “(C_(3-n))cycloalkyl” as used herein, either alone or incombination with another radical, means saturated cyclic hydrocarbonradicals containing from three to n carbon atoms. The term“(C₃₋₇)cycloalkyl” includes cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl and cycloheptyl.

The terms “(C_(1-n))alkoxy” or “O—(C_(1-n))alkyl” as used hereininterchangeably, mean a straight chain alkyl containing from one to ncarbon atoms linked through an oxygen atom or a branched chain alkylradical containing three to n carbon atoms linked through an oxygenatom. Examples of (C₁₋₆)alkoxy include, but are not limited to, methoxy(CH₃O—), ethoxy (CH₃CH₂O—), propoxy (CH₃CH₂CH₂O—), 1-methylethoxy((CH₃)₂CHO—), butoxy (CH₃CH₂CH₂CH₂O—) and 1,1-dimethylethoxy((CH₃)₃CO—). The latter radical is known commonly as tert-butoxy.

When a (C_(1-n))alkoxy group is substituted with one or moresubstituents, for example, aryl or heteroaryl substituents, saidsubstituents are attached to the alkyl portion of the alkoxy group.

The term “(C_(1-n))haloalkyl” as used herein means an alkyl radicalcontaining one to n carbon atoms wherein one or more hydrogen atoms arereplaced by a halogen atom (e.g. trifluoromethyl).

The terms “(C_(1-n))alkylthio” or “S—(C_(1-n))alkyl” as used hereininterchangeably, mean a straight chain alkyl containing one to n carbonatoms linked through a sulfur atom, or a branched chain alkyl radicalcontaining three to n carbon atoms linked through a sulfur atom.Examples of (C_(1-n))alkylthio include, but are not limited to,methylthio (CH₃S—), ethylthio (CH₃CH₂S—), propylthio (CH₃CH₂CH₂S—),1-methylethylthio ((CH₃)₂CHS—), butylthio (CH₃CH₂CH₂CH₂S—) and1,1-dimethylethylthio ((CH₃)₃CS—).

The term “amino” as used herein means an amino radical of formula —NH₂.The term “(C_(1-n))alkylamino” as used herein means an alkylaminoradical containing one to n carbon atoms and includes, but is notlimited to, methylamino, propylamino, (1-methylethyl)amino and(2-methylbutyl)amino. The term “di((C_(1-n))alkyl)amino” means an aminoradical having two identical or different (C_(1-n))alkyl substituentsand includes, but is not limited to, dimethylamino, diethylamino,ethylmethylamino and the like.

The term “aryl” as used herein, either alone or in combination withanother radical, means a phenyl ring which is optionally fused to asecond carbocyclic ring, wherein said carbocyclic ring contains 5 to 7carbon atoms and may be saturated, unsaturated or aromatic. For example,aryl includes, but is not limited to, phenyl, naphthyl,

The terms “aryloxy” or “O-aryl” as used herein interchangeably, mean anaryl as defined above linked though an oxygen atom. Examples of aryloxyinclude, but are not limited to, phenoxy.

The term “(C_(1-n))alkyl-aryl” as used herein, either alone or incombination with another radical, means an aryl as defined above linkedthrough an alkyl group, wherein alkyl is as defined above containingfrom 1 to n carbon atoms. (C₁₋₆)alkyl-aryl includes, but is not limitedto, benzyl and phenylbutyl.

The term “Het” or “heterocycle” as used herein means a monovalentradical derived by removal of a hydrogen from a four- to seven-membered,saturated or unsaturated (including aromatic) ring system containingfrom one to three heteroatoms independently selected from nitrogen,oxygen and sulfur. Optionally, the heterocycle may bear one or twosubstituents; for example, N-oxido, (C₁₋₆)alkyl, (C₁₋₃)alkyl-phenyl,(C₁₋₆)alkoxy, halo, amino or (C₁₋₆)alkylamino. Again optionally, thefour- to seven-membered heterocycle can be fused to a second ring systemwhich may be saturated or unsaturated (including aromatic) and which maybe carbocyclic or may contain from one to three heteroatomsindependently selected from nitrogen, oxygen and sulfur. Examples ofsuch a second ring system include, but are not limited to, a cycloalkyl,an aryl (e.g. phenyl) or another heterocycle.

Examples of suitable heterocycles and optionally substitutedheterocycles include, but are not limited to, morpholine, thiadiazole,quinoline, benzodioxole, benzothiazole, pyrrolidine, tetrahydrofuran,thiazolidine, pyrrole, indole, benzimidazole, 1H-imidazole,1-methyl-1H-imidazole, pyrazole, furan, thiophene, oxazole, isoxazole,thiazole, 2-methylthiazole, 2-aminothiazole, 2-(methylamino)thiazole,piperidine, 1-methylpiperidine, 1-methylpiperazine, 1,4-dioxane,pyridine, pyridine N-oxide, pyrimidine, 2,4-dihydroxypyrimidine,2,4-dimethylpyrimidine, 2,6-dimethylpyridine, 1-methyl-1H-tetrazole,2-methyl-2H-tetrazole, benzoxazole and thiazolo[4,5-b]-pyridine.

The term “(C_(1-n))alkyl-heterocycle” as used herein means a heterocycleas defined above linked through a (C_(1-n))alkyl chain, also as definedabove.

The term “heteroaryl” as used herein means a monovalent radical derivedby removal of a hydrogen from a five- or six-membered, aromatic ringsystem containing from one to three heteroatoms independently selectedfrom nitrogen, oxygen and sulfur. Optionally, the heteroaryl may bearone or two substituents; for example, N-oxido, (C₁₋₆)alkyl,(C₁₋₃)alkyl-phenyl, (C₁₋₆)alkoxy, halo, amino or (C₁₋₆)alkylamino. Againoptionally, the five- or six-membered heteroaryl can be fused to asecond aromatic ring system which may be carbocyclic or may contain fromone to three heteroatoms independently selected from nitrogen, oxygenand sulfur. Examples of such a second ring system include, but are notlimited to, aryl (e.g. phenyl) or another heteroaryl. Specifically,heteroaryl includes but is not limited to: indole, benzimidazole,imidazole, furan, thiophene, pyrrole, oxazole, pyridine and pyrimidine.

The term “(C_(1-n))alkyl-heteroaryl” as used herein means a heteroarylas defined above, linked through a (C_(1-n))alkyl chain, also as definedabove.

As used herein, the designation whereby a bond is drawn as emanatingfrom the center of a ring, such as, for example,

means that the bond may be attached to any free position on the ringthat would otherwise be substituted by a hydrogen atom, unless specifiedotherwise. Such bonds may be linked to substituents of the ring or mayindicate the linkage of the ring as a substituent on another structure.

As used herein, the term “detectable label” means any group that may belinked to a compound of the present invention such that when thecompound is associated with the target, for example, the transcriptionalactivation domain of a papillomavirus E2 protein, such label allowsrecognition either directly or indirectly of the compound such that itcan be detected, measured and quantified. Examples of such “labels” areintended to include, but are not limited to, fluorescent labels,chemiluminescent labels, colorimetric labels, enzymatic markers,radioactive isotopes and affinity tags such as biotin. Such labels areattached to the compound or to the protein by well known methods.

As used herein, the term “affinity tag” means a ligand (that may belinked to a compound of the present invention) whose strong affinity fora receptor can be used to extract from a solution the entity to whichthe ligand is attached. Examples of such ligands include, but are notlimited to, biotin or a derivative thereof, a histidine polypeptide, apolyarginine, an amylose sugar moiety or a defined epitope recognizableby a specific antibody. Such affinity tags are attached to the compoundby well-known methods.

As used herein, the term “photoreactive group” means a group that istransformed, upon activation by light, from an inert group to a reactivespecies, such as a free radical. Such a group may be used as, forexample, a photoaffinity label. Examples of such groups include, but arenot limited to, benzophenones, azides, and the like.

The term “pharmaceutically acceptable carrier” as used herein means anon-toxic, generally inert vehicle for the active ingredient which doesnot adversely affect the ingredient.

The term “effective amount” means a predetermined antiviral amount ofthe antiviral agent, i.e. an amount of the agent sufficient to beeffective against the virus in vivo.

As used herein, the term “treatment” means the administration of acompound or composition according to the present invention to alleviateor eliminate symptoms of papillomavirus infection and/or to reduce viralload in a patient.

As used herein, the term “prevention” means the administration of acompound or composition according to the present invention post-exposureof the individual to the virus but before the appearance of symptoms ofthe disease, to prevent the appearance of symptoms of the disease.

The compounds of the present invention can be obtained in the form oftherapeutically acceptable salts. The term “pharmaceutically acceptablesalt” as used herein includes those derived from pharmaceuticallyacceptable bases. Examples of suitable bases include choline,ethanolamine and ethylenediamine. Na⁺, K⁺, and Ca⁺⁺ salts are alsocontemplated to be within the scope of the invention (also seePharmaceutical salts, Birge, S. M. et al., J. Pharm. Sci. (1977), 66,1-19).

The term “pharmaceutically acceptable ester” as used herein, eitheralone or in combination with another radical, means esters of a compoundin which the carboxyl function is replaced by an alkoxycarbonylfunction:

in which the R moiety of the ester is selected from alkyl (e.g. methyl,ethyl, n-propyl, tert-butyl, n-butyl); alkoxyalkyl (e.g. methoxymethyl);acyloxyalkyl (e.g. acetoxymethyl); (C₁₋₆)alkyl-aryl (e.g. benzyl);aryloxyalkyl (e.g. phenoxymethyl); aryl (e.g. phenyl), optionallysubstituted with halogen, (C₁₋₄)alkyl or (C₁₋₄)alkoxy. Other suitableprodrug esters can be found in Design of prodrugs, Bundgaard, H. Ed.Elsevier (1985). Such pharmaceutically acceptable esters are usuallyhydrolyzed in vivo when injected in a mammal and transformed into theacid form of the compound of formula (I).

With regard to the esters described above, unless otherwise specified,any alkyl moiety present advantageously contains 1 to 16 carbon atoms,particularly 1 to 6 carbon atoms. Any aryl moiety present in such estersadvantageously comprises a phenyl group.

In particular the esters may be a (C₁₋₆)alkyl ester, an unsubstitutedbenzyl ester or a benzyl ester substituted with at least one halogen,(C₁₋₆)alkyl, (C₁₋₆)alkoxy, nitro or trifluoromethyl.

Preferred Embodiments

Compounds

According to an alternative embodiment, the invention provides acompound of formula (I) or its enantiomers or diastereoisomers thereof:

wherein R¹ is H, (C₁₋₆)alkyl, halo, (C₁₋₆)haloalkyl, (C₁₋₆)alkoxy,(C₁₋₆)alkylthio, amino, (C₁₋₆)alkylamino, di((C₁₋₆)alkyl)amino,(C₃₋₇)cycloalkyl, phenyl, or 5- or 6-membered heterocycle;

-   X₁ is CR² or N;-   each R² is independently selected from: H, (C₁₋₆)alkyl, halo,    (C₁₋₆)haloalkyl, (C₁₋₆)alkoxy, (C₁₋₆)alkylthio, amino,    (C₁₋₆)alkylamino or di((C₁₋₆)alkyl)amino;-   A is (C₃₋₇)cycloalkyl, (C₆ or C₁₀)aryl or heterocycle, all of which    being optionally substituted with:    -   (C₁₋₆)alkyl, halo, (C₁₋₆)haloalkyl, (C₁₋₆)alkoxy,        (C₁₋₆)alkylthio, amino, (C₁₋₆)alkylamino, or        di((C₁₋₆)alkyl)amino, aryl, O-aryl, S-aryl, NH-aryl,        (C₁₋₆)alkyl-aryl, heteroaryl, O-heteroaryl, S-heteroaryl,        NH-heteroaryl or (C₁₋₆)alkyl-heteroaryl;-   or A is NHR³ or N(R³)₂ wherein    -   R³ is independently selected from H, (C₁₋₆)alkyl,        (C₃₋₇)cycloalkyl, aryl and heteroaryl;-   R⁴ is (C₁₋₆)alkyl, (C₃₋₇)cycloalkyl, (C₆ or C₁₀)aryl, heterocycle,    (C₁₋₆)alkyl-aryl or (C₁₋₆)alkyl-heterocycle, all of which being    optionally substituted with:    -   (C₁₋₆)alkyl, halo, (C₁₋₆)haloalkyl, (C₁₋₆)alkoxy,        (C₁₋₆)alkylthio, amino, (C₁₋₆)alkylamino, di((C₁₋₆)alkyl)amino,        aryl, heteroaryl, (C₁₋₆)alkyl-aryl, (C₁₋₆)alkyl-heteroaryl,        (C₁₋₆)alkoxy-aryl or (C₁₋₆)alkoxy-heteroaryl;-   or wherein the (C₆)aryl is fused with a saturated or unsaturated 4-    to 6-membered ring optionally containing one to three heteroatoms    selected from N, O, and S;-   Z is O or S;-   Y is CH₂, NH or O;-   B is selected from:-    wherein R⁵ is H, (C₁₋₆)alkyl, (C₃₋₇)cycloalkyl, halo,    (C₁₋₆)haloalkyl, (C₁₋₆)alkoxy, (C₁₋₆)alkylthio, amino,    (C₁₋₆)alkylamino, di((C₁₋₆)alkyl)amino, hydroxyl or sulfhydryl;-   X₂ is CR⁷ or N;-   R⁶ and R⁷ are independently H, (C₁₋₆)alkyl, halo, (C₁₋₆)haloalkyl,    (C₁₋₆)alkoxy, (C₁₋₆)alkylthio, amino, (C₁₋₆)alkylamino,    di((C₁₋₆)alkyl)amino, hydroxyl or sulfhydryl; or, when X₂ is CR⁷, R₆    and R⁷ are optionally bonded together to form a saturated or    unsaturated 5- or 6-membered ring optionally containing one or two    heteroatoms selected from S, O and N;-   X₃ is O, S or NR⁸, wherein R⁸ is H or (C₁₋₆)alkyl; and-   R^(c) is COOH, CONHR⁹, SO₂NHR⁹, or tetrazolyl,    -   wherein R⁹ is H, (C₁₋₆)alkyl, (C₃₋₆)cycloalkyl or phenyl;-   provided that R⁵ and R⁶ cannot both together be H and when R⁵ or R⁶    is H, then R¹ is not H, and provided that when Y is NH, R⁶ cannot be    hydroxyl or sulfhydryl;    or a pharmaceutically-acceptable salt or ester thereof.

According to a preferred embodiment, the invention provides a compoundof Formula (I) or an enantiomer thereof, a diastereoisomer thereof, or apharmaceutically-acceptable ester or salt thereof,

wherein R¹ is H, (C₁₋₆)alkyl, halo, (C₁₋₆)haloalkyl, (C₁₋₆)alkoxy,(C₁₋₆)alkylthio, amino, (C₁₋₆)alkylamino, di((C₁₋₆)alkyl)amino,(C₃₋₇)cycloalkyl, phenyl, or 5- or 6-membered heteroaryl;

-   X₁ is CR² or N;-   one or both free positions on the phenyl ring may be substituted    with R² and each R² is independently selected from: H, (C₁₋₆)alkyl,    halo, (C₁₋₆)haloalkyl, (C₁₋₆)alkoxy, (C₁₋₆)alkylthio, amino,    (C₁₋₆)alkylamino and di((C₁₋₆)alkyl)amino;-   A is (C₃₋₇)cycloalkyl, phenyl, or a 5- or 6-membered monocyclic    heterocycle, each of which being optionally substituted with one or    more substituents independently selected from:    -   (C₁₋₆)alkyl, halo, (C₁₋₆)haloalkyl, (C₁₋₆)alkoxy,        (C₁₋₆)alkylthio, amino, (C₁₋₆)alkylamino, di((C₁₋₆)alkyl)amino        and aryloxy;-   or A is NHR³ or N(R³)₂ wherein    -   each R³ is independently selected from: H, (C₁₋₆)alkyl,        (C₃₋₇)cycloalkyl, aryl and heteroaryl;-   R⁴ is (C₁₋₆)alkyl, (C₃₋₇)cycloalkyl, aryl, heteroaryl,    (C₁₋₆)alkyl-aryl or (C₁₋₆)alkyl-heteroaryl, each of which being    optionally substituted with one or more substituents independently    selected from:    -   (C₁₋₆)alkyl, halo, (C₁₋₆)haloalkyl, (C₁₋₆)alkylthio, amino,        (C₁₋₆)alkylamino, di((C₁₋₆)alkyl)amino, aryl, heteroaryl,        (C₁₋₆)alkyl-aryl, (C₁₋₆)alkyl-heteroaryl, and (C₁₋₆)alkoxy,        wherein said (C₁₋₆)alkoxy is optionally substituted with aryl or        heteroaryl;-   or R⁴ is phenyl fused with a saturated or unsaturated 4- to    6-membered ring optionally containing one to three heteroatoms    independently selected from N, O, and S;-   Z is O or S;-   Y is CH₂ or NH;-   B is selected from:-    wherein R⁵ is H, (C₁₋₆)alkyl, halo, (C₁₋₆)haloalkyl, (C₁₋₆)alkoxy,    (C₁₋₆)alkylthio, amino, (C₁₋₆)alkylamino, di((C₁₋₆)alkyl)amino,    hydroxyl or sulfhydryl;-   X₂ is CR⁷ or N;-   R⁶ and R⁷ are independently H, (C₁₋₆)alkyl, halo, (C₁₋₆)haloalkyl,    (C₁₋₆)alkoxy, (C₁₋₆)alkylthio, amino, (C₁₋₆)alkylamino,    di((C₁₋₆)alkyl)amino, hydroxyl or sulfhydryl; or, when X₂ is CR⁷, R⁶    and R⁷ are optionally bonded together to form a saturated or    unsaturated 5- or 6-membered ring optionally containing one or two    heteroatoms independently selected from S, O and N;-   X₃ is O, S or NR⁸, wherein R⁸ is H or (C₁₋₆)alkyl; and-   R^(c) is COOH, CONHR⁹, SO₂NHR⁹, or tetrazolyl;    -   wherein R⁹ is H, (C₁₋₆)alkyl, (C₃₋₆)cycloalkyl or phenyl;-   provided that, R⁵ and R⁶ cannot both together be H and when R⁵ or R⁶    is H, then R¹ is not H, and provided that when Y is NH, R⁶ cannot be    hydroxyl or sulfhydryl.

More preferably, compounds of the present invention are those of formula(I) or an enantiomer thereof, a diastereoisomer thereof, or apharmaceutically-acceptable ester or salt thereof,

wherein R¹ is H, (C₁₋₆)alkyl, halo, (C₁₋₆)haloalkyl, (C₁₋₆)alkoxy,(C₁₋₆)alkylthio, amino, (C₁₋₆)alkylamino, or di((C₁₋₆)alkyl)amino;

-   X₁ is CR² or N;-   one or both free positions on the phenyl ring may be substituted    with R² and each R² is independently selected from: H or halo;-   A is (C₃₋₇)cycloalkyl, phenyl, or a 5- or 6-membered monocyclic    heterocycle, each of which being optionally substituted with one or    more substituents independently selected from:    -   (C₁₋₆)alkyl, halo, (C₁₋₆)haloalkyl, (C₁₋₆)alkoxy,        (C₁₋₆)alkylthio, amino, (C₁₋₆)alkylamino, di((C₁₋₆)alkyl)amino        and aryloxy;-   or A is NHR³ or N(R³)₂ wherein    -   each R³ is independently selected from: H, (C₁₋₆)alkyl,        (C₃₋₇)cycloalkyl, aryl and heteroaryl;-   R⁴ is (C₁₋₆)alkyl, (C₃₋₇)cycloalkyl, aryl, heteroaryl,    (C₁₋₆)alkyl-aryl or (C₁₋₆)alkyl-heteroaryl, each of which being    optionally substituted with one or more substituents independently    selected from:    -   (C₁₋₆)alkyl, halo, (C₁₋₆)haloalkyl, (C₁₋₆)alkylthio, amino,        (C₁₋₆)alkylamino, di((C₁₋₆)alkyl)amino, aryl, heteroaryl,        (C₁₋₆)alkyl-aryl, (C₁₋₆)alkyl-heteroaryl, and (C₁₋₆)alkoxy,        wherein said (C₁₋₆)alkoxy is optionally substituted with aryl or        heteroaryl; or    -   R⁴ is phenyl fused with a saturated or unsaturated 4- to        6-membered ring optionally containing one to three heteroatoms        independently selected from N, O, and S;-   Z is O;-   Y is CH₂ or NH;-   B is selected from:-    wherein R⁵ is H, (C₁₋₆)alkyl, halo, (C₁₋₆)haloalkyl, (C₁₋₆)alkoxy,    (C₁₋₆)alkylthio, (C₁₋₆)alkylamino, or di((C₁₋₆)alkyl)amino;-   X₂ is N or CR⁷;-   R⁶ and R⁷ are independently H, (C₁₋₆)alkyl, halo, (C₁₋₆)haloalkyl,    (C₁₋₆)alkoxy, (C₁₋₆)alkylthio, (C₁₋₆)alkylamino, and    di((C₁₋₆)alkyl)amino, or, when X₂ is CR⁷, R⁶ and R⁷ are optionally    bonded together to form a saturated or unsaturated 5- or 6-membered    ring, optionally containing one or two heteroatoms independently    selected from S, O and N;-   X₃ is O, S or NR⁸, wherein R⁸ is H or (C₁₋₆)alkyl; and-   R¹ is COOH or SO₂NH₂;-   provided that, R⁵ and R⁶ cannot both together be H and when R⁵ or R⁶    is H, then R¹ is not H.

Most preferably, compounds of the present invention are those of formula(I) or an enantiomer thereof, a diastereoisomer thereof, or apharmaceutically-acceptable ester or salt thereof,

wherein R¹ is (C₁₋₆)alkyl;

-   X₁ is CH;-   R² is H;-   A is (C₃₋₇)cycloalkyl, phenyl, or a 5- or 6-membered monocyclic    heterocycle, each of which being optionally substituted with one or    more substituents independently selected from (C₁₋₆)alkyl, halo,    (C₁₋₆)haloalkyl or aryloxy;-   or A is NHR³ or N(R³)₂ wherein each R³ is independently selected    from (C₁₋₆)alkyl, (C₃₋₇)cycloalkyl, aryl, and heteroaryl;-   R⁴ is aryl, or heteroaryl, both optionally substituted with one or    more substituents independently selected from:    -   (C₁₋₆)alkyl, halo, (C₁₋₆)haloalkyl, (C₁₋₆)alkylthio, amino,        (C₁₋₆)alkylamino, di((C₁₋₆)alkyl)amino, aryl, heteroaryl, and        (C₁₋₆)alkoxy, wherein said (C₁₋₆)alkoxy is optionally        substituted with aryl or heteroaryl;-   or R⁴ is phenyl fused with a saturated or unsaturated 4- to    6-membered ring optionally containing one or two heteroatoms    independently selected from N, O, and S;-   Z is O;-   Y is CH₂;-   B is:-    wherein R⁵ is (C₁₋₆)alkoxy;-   X₂ is CR⁷;-   R⁶ is (C₁₋₆)alkyl, halo or (C₁₋₆)haloalkyl, and R⁷ is H; or R⁶ and    R⁷ are optionally bonded together to form a saturated or unsaturated    5- or 6-membered ring, optionally containing one or two heteroatoms    independently selected from S, O and N.

With respect to the compounds of formula (I), alternatively, morepreferably, R¹ is methyl or ethyl.

Alternatively, more preferably, A is cyclohexyl, phenyl, 1-piperidinyl,4-morpholinyl, N(H)cyclohexyl or N(CH₃)cyclohexyl, said cyclohexyl,phenyl, 1-piperidinyl and 4-morpholinyl being optionally mono- ordi-substituted with: (C₁₋₆)alkyl, halo, (C₁₋₆)haloalkyl or phenoxy.

Alternatively, more preferably, A is cyclohexyl.

Alternatively, more preferably, A is phenyl.

Alternatively, more preferably, A is 1-piperidinyl or 4-morpholinyl,each optionally mono- or di-substituted with: (C₁₋₆)alkyl, halo,(C₁₋₆)haloalkyl or phenoxy.

Alternatively, more preferably, A is N(H)cyclohexyl or N(CH₃)cyclohexyl.

Alternatively, even more preferably, A is 1-piperidinyl optionally mono-or di-substituted with halo or phenoxy, and R¹ is H or (C₁₋₆)alkyl.

Alternatively even more preferably, A is 1-piperidinyl and R¹ is H, CH₃,or ethyl.

Alternatively more preferably, R⁴ is thienyl, furanyl or naphthyloptionally substituted with one or more substituents independentlyselected from methoxy and (C₁₋₆)alkyl.

Alternatively more preferably, R⁴ is phenyl, optionally substituted withone to four substituents independently selected from: methoxy, halo, andphenyl, or R⁴ is phenyl fused with a saturated or unsaturated 4- to6-membered ring optionally containing one to three heteroatomsindependently selected from N, O, and S.

Alternatively more preferably, R⁵ is methoxy or ethoxy.

Alternatively preferably, R⁶ is alkyl or halo. Alternatively even morepreferably, R⁶ is halo.

Alternatively preferably, X₂ is CR⁷, wherein R⁷ and R⁶ are bondedtogether to form an unsaturated 6-membered ring which optionallycontains one or two heteroatoms independently selected from S, O and N.

Alternatively more preferably, X₂ is CR⁷, wherein R⁷ and R⁶ are bondedtogether to form a phenyl ring.

Alternatively preferably, compounds of the present invention are thoseof formula (I) wherein:

-   R¹ is H, methyl, or ethyl;-   both X₁ and X₂ are CH;-   one or both free positions on the phenyl ring may be substituted    with R² and each R² is independently selected from: H and halo;-   A is cyclohexyl, phenyl, 1-piperidyl, 4-morpholinyl, N(H)cyclohexyl,    or N(CH₃)cyclohexyl, said cyclohexyl, phenyl, 1-piperidyl and    4-morpholinyl being optionally mono- or di-substituted with:    (C₁₋₆)alkyl, halo, (C₁₋₆)haloalkyl, and aryloxy;-   R⁴ is aryl, or heteroaryl, both optionally substituted with one or    more substituents independently selected from:    -   (C₁₋₆)alkyl, halo, (C₁₋₆)haloalkyl, (C₁₋₆)alkylthio, amino,        (C₁₋₆)alkylamino, di((C₁₋₆)alkyl)amino, aryl, heteroaryl, and        (C₁₋₆)alkoxy, wherein said (C₁₋₆)alkoxy is optionally        substituted with aryl or heteroaryl;-   or R⁴ is phenyl fused with a saturated or unsaturated 4- to    6-membered ring optionally containing one or two heteroatoms    independently selected from N, O, and S;-   Z is O;-   Y is CH₂ or NH;-   B is:-   R⁵ is methoxy or ethoxy;-   R⁶ is halo; and-   R^(c) is COOH.

Alternatively more preferably, compounds of the present invention arethose of formula (I) wherein:

-   R¹ is H or methyl;-   X₁ is CH;-   R² is H;-   A is 4-morpholinyl, N(H)cyclohexyl, N(CH₃)cyclohexyl or    1-piperidinyl, said 4-morpholinyl and 1-piperidinyl being optionally    substituted with Me or phenoxy or optionally geminally    difluorinated;-   R⁴ is thienyl, furanyl or naphthyl optionally substituted with one    or more substituents independently selected from: methoxy and    (C₁₋₆)alkyl, or R⁴ is phenyl optionally substituted with one to four    of: methoxy, halo, or phenyl, or-   R⁴ is phenyl fused with a saturated or unsaturated 4- to 6-membered    ring optionally containing one to three heteroatoms independently    selected from N, O, and S;-   Z is O;-   Y is CH₂;-   B is:-   R⁵ is methoxy;-   X₂ is CH;-   R⁶ is bromo; and-   R^(c) is COOH.

Alternatively preferably, the compounds of the present invention arethose of formula (III):

wherein R¹, R², A, R⁴, Y, R⁵, and R⁶ are as defined herein, particularlyin Table 1 below.

Alternatively more preferably, the compounds of the present inventionare those of formula (IV):

wherein Y and R⁶ are as defined herein, particularly in Table 2 below,and R⁴⁰, R⁴¹, R⁴², R⁴³, and R⁴⁴ are each independently selected from H,—CH₃, —CH(CH₃)₂—C(CH₃)₃, —OCH₃, —N(CH₃)₂, —SCH₃, —CF₃, chloro, fluoro,phenyl, and

Alternatively more preferably, the compounds of the present inventionare those of formula (V):

wherein R¹, A, R⁴, Y, R⁵, R⁶, X₂ and R^(c) are as defined herein,particularly in Table 3 below.

Alternatively preferably, the compounds of the present invention arethose of formula (VI):

wherein R¹, A, R⁴, Z, Y, X₃ and R^(c) are as defined herein,particularly in Table 4 below.

The compounds of the present invention can be synthesized as mixtures ofstereoisomers and then separated into their respective singlestereoisomers. All such stereoisomers are contemplated as being withinthe scope of the present invention.

Specific Embodiments

Included within the scope of this invention is each single compound,including its enantiomers and diastereomers, presented in Tables 1 to 4below.

Anti-Papilloma Virus Activity

According to a second embodiment of the present invention, compounds ofthe present invention are useful in the treatment or prevention ofpapilloma virus infections, particularly human papilloma virusinfection.

According to this second embodiment of the present invention, preferredcompounds of formula (II) are provided:

wherein R¹¹ is H, (C₁₋₆)alkyl, halo, (C₁₋₆)haloalkyl, (C₁₋₆)alkoxy,(C₁₋₆)alkylthio, amino, (C₁₋₆)alkylamino, di((C₁₋₆)alkyl)amino,(C₃₋₇)cycloalkyl, phenyl, or 5- or 6-membered heteroaryl;

-   X₄, & and X₆ are independently chosen from CR¹² and N;    -   each R¹² is independently selected from: H, (C₁₋₆)alkyl,        (C₁₋₆)alkoxy, halo, (C₁₋₆)alkylthio, (C₁₋₆)haloalkyl, amino,        (C₁₋₆)alkylamino and di((C₁₋₆)alkyl)amino;-   R¹³ is (C₁₋₆)alkyl, (C₃₋₇)cycloalkyl, phenyl, or 5- or 6-membered    monocyclic heterocycle, wherein said (C₁₋₆)alkyl, (C₃₋₇)cycloalkyl,    phenyl, and 5- or 6-membered monocyclic heterocycle may be    optionally substituted with R¹⁵; wherein    -   R¹⁵ is independently selected from H, (C₁₋₆)alkyl,        (C₃₋₇)cycloalkyl, (C₁₋₆)alkoxy, (C₁₋₆)alkylthio, amino,        (C₁₋₆)alkylamino, di((C₁₋₆)alkyl)amino, aryl, aryloxy, and        heteroaryl;-   or R³ is —OR¹⁶, SR¹⁶, NHR¹⁶ or N(R⁶)₂, wherein    -   R¹⁶ is independently selected in each instance from H,        (C₁₋₆)alkyl, (C₃₋₇)cycloalkyl, aryl and heteroaryl;-   R¹⁴ is H, (C₁₋₆)alkyl, (C₃₋₇)cycloalkyl, aryl, heteroaryl,    (C₁₋₆)alkyl-aryl and (C₁₋₆)alkyl-heteroaryl, wherein the    (C₁₋₆)alkyl, (C₃₋₇)cycloalkyl, aryl, heteroaryl, (C₁₋₆)alkyl-aryl    and (C₁₋₆)alkyl-heteroaryl are optionally substituted with one or    more substituents independently selected from:    -   (C₁₋₆)alkyl, halo, (C₁₋₆)haloalkyl, (C₁₋₆)alkylthio, amino,        (C₁₋₆)alkylamino, di((C₁₋₆)alkyl)amino, aryl, heteroaryl,        (C₁₋₆)alkyl-aryl, (C₁₋₆)alkyl-heteroaryl, and (C₁₋₆)alkoxy,        wherein said (C₁₋₆)alkoxy is optionally substituted with aryl or        heteroaryl;-   or R¹⁴ is phenyl fused with a saturated or unsaturated 4- to    6-membered ring optionally containing one to four heteroatoms    independently selected from N, O, and S;-   W is NH;-   Y is CH₂, NH or O;-   Z is O or S;-   T is aryl, or heteroaryl, wherein said aryl, or heteroaryl are    optionally substituted at one to three positions with R¹¹, hydroxyl    or sulfhydryl; and-   R¹⁸ is COOH, COOR¹⁹, CONHR¹⁹, SO₂NHR¹⁹ or tetrazolyl; wherein    -   R¹⁹ is H, (C₁₋₆)alkyl, (C₃₋₆)cycloalkyl or phenyl.

Preferably, compounds of the present invention of formula (II) areuseful in the treatment or prevention of papilloma virus infections,particularly human papilloma virus infection.

According to a preferred aspect of this second embodiment of the presentinvention, compounds of formula II are provided or its enantiomers ordiastereoisomers thereof, in the manufacture of a medicament for thetreatment or prevention of a papilloma virus infection in a mammal:

wherein R¹¹ is H, (C₁₋₆)alkyl, halo, (C₁₋₆)haloalkyl, (C₁₋₆)alkoxy,(C₁₋₆)alkylthio, amino, (C₁₋₆)alkylamino, di((C₁₋₆)alkyl)amino,(C₃₋₇)cycloalkyl, phenyl, or 5- or 6-membered heteroaryl;

-   X₄, X₅ and X₆ are independently chosen from CR¹² and N;    -   each R¹² is independently selected from: H, (C₁₋₆)alkyl,        (C₁₋₆)alkoxy, halo, (C₁₋₆)alkylthio, (C₁₋₆)haloalkyl, amino,        (C₁₋₆)alkylamino and di((C₁₋₆)alkyl)amino;-   R¹³ is (C₁₋₆)alkyl, (C₃₋₇)cycloalkyl, phenyl, or 5- or 6-membered    monocyclic heterocycle, wherein said (C₁₋₆)alkyl, (C₃₋₇)cycloalkyl,    phenyl, 5- or 6-membered monocyclic heterocycle, may be optionally    substituted with R¹⁵; wherein    -   R¹⁵ is independently selected from H, (C₁₋₆)alkyl,        (C₃₋₇)cycloalkyl, (C₁₋₆)alkoxy, (C₁₋₆)alkylthio, amino,        (C₁₋₆)alkylamino, di((C₁₋₆)alkyl)amino, aryl, aryloxy, and        heteroaryl;-   or R¹³ is —OR¹⁶, SR¹⁶, NHR¹⁶ or N(R⁶)₂, wherein    -   R¹⁶ is independently selected in each instance from H,        (C₁₋₆)alkyl, (C₃₋₇)cycloalkyl, aryl and heteroaryl;-   R¹⁴ is H, (C₁₋₆)alkyl, (C₃₋₇)cycloalkyl, aryl, heteroaryl,    (C₁₋₆)alkyl-aryl and (C₁₋₆)alkyl-heteroaryl, wherein the    (C₁₋₆)alkyl, (C₃₋₇)cycloalkyl, aryl, heteroaryl, (C₁₋₆)alkyl-aryl    and (C₁₋₆)alkyl-heteroaryl are optionally substituted with one or    more substituents independently selected from:    -   (C₁₋₆)alkyl, halo, (C₁₋₆)haloalkyl, (C₁₋₆)alkylthio, amino,        (C₁₋₆)alkylamino, di((C₁₋₆)alkyl)amino, aryl, heteroaryl,        (C₁₋₆)alkyl-aryl, (C₁₋₆)alkyl-heteroaryl, and (C₁₋₆)alkoxy,        wherein said (C₁₋₆)alkoxy is optionally substituted with aryl or        heteroaryl;-   or R¹⁴ is phenyl fused with a saturated or unsaturated 4- to    6-membered ring optionally containing one to four heteroatoms    independently selected from N, O, and S;-   W is NH;-   Y is CH₂, NH or O;-   Z is O or S;-   T is aryl, or heteroaryl, wherein said aryl, or heteroaryl are    optionally substituted at one to three positions with R¹¹, hydroxyl    or sulfhydryl, with the proviso that T is not a pyrimidine; and-   R¹⁸ is COOH, COOR¹⁹, CONHR¹⁹, SO₂NHR¹⁹ or tetrazolyl; wherein    -   R¹⁹ is H, (C₁₋₆)alkyl, (C₃₋₆)cycloalkyl or phenyl.

More preferably, compounds of the present invention of formula (I) areuseful in the treatment or prevention of papilloma virus infections,particularly human papilloma virus infection.

Alternatively more preferably, compounds of the present invention offormula (III) are useful in the treatment or prevention of papillomavirus infections, particularly human papilloma virus infection.

Alternatively more preferably, compounds of the present invention offormula (IV) are useful in the treatment or prevention of papillomavirus infections, particularly human papilloma virus infection.

Alternatively more preferably, compounds of the present invention offormula (V) are useful in the treatment or prevention of papilloma virusinfections, particularly human papilloma virus infection.

Alternatively more preferably, compounds of the present invention offormula (VI) are useful in the treatment or prevention of papillomavirus infections, particularly human papilloma virus infection.

The antiviral activity of the compounds of the present invention can bedemonstrated by biochemical and biological procedures showing theinhibitory effect of the compounds on viral DNA replication.

Preferably, the compounds of the present invention described above areinhibitory against papilloma viruses, preferably human papillomavirus(HPV). More preferably the compounds are active against HPV low risk orhigh risk type. Even more preferably, the compounds are active againstlow risk type HPV (i.e. type 6 and type 11, and especially HPV type 11).Alternatively, the high-risk type is selected from the group consistingof types 16, 18, 31, 33, 35, 45, 52, or 58, preferably, type 16). Mostpreferably, the compounds of the invention are directed against HPVtypes 6 and 11, even most preferably, against HPV-11.

A biochemical procedure for demonstrating anti-papilloma virus activityfor the compounds of the present invention is described in the exampleshereinafter. This particular assay determines the ability of a testcompound to inhibit the activity (IC₅₀) of HPV-11 DNA replication. Morespecifically, in the assay described herein, the inhibitory activity ofthe test compound is evaluated based on its ability to interfere withthe E1-E2-DNA origin of replication interaction, thereby inhibitinginitiation of viral DNA replication. The protein-protein interactionbetween E1 and E2 was found to be the specific target of these compoundsby testing them in the assays as described in: White et al., J. Biol.Chem. 2003, 278(29), p. 26765-26772.

When a compound of the present invention or one of its therapeuticallyacceptable salts, is employed as an antiviral agent, it may beadministered orally, topically or parenterally to mammals, e.g. humans,rabbits or mice, alone or in a vehicle comprising one or morepharmaceutically acceptable carriers, the proportion of which isdetermined by the solubility and chemical nature of the compound, chosenroute of administration and standard biological practice.

Whether it be termed treatment or prevention, a compound of the presentinvention may also be used to prevent perinatal transmission of HPV frommother to baby, by administration to the mother prior to giving birth.More specifically, a compound of the present invention may be used toprevent laryngeal papillomatosis in the baby.

For oral administration, the compound or a therapeutically acceptablesalt thereof can be formulated in unit dosage forms such as capsules ortablets each containing a predetermined amount of the active ingredient,ranging from about 1 to 1000 mg, alternatively ranging from about 25 toabout 1000 mg, in a pharmaceutically acceptable carrier.

For topical administration, the compound may be formulated inpharmaceutically accepted vehicles containing 0.1 to 5 percent,preferably 0.5 to 5 percent, of the active agent. Such formulations canbe in the form of a solution, cream or lotion.

For parenteral administration, the compound of the present invention maybe administered by either intravenous, subcutaneous or intramuscularinjection, in combination with pharmaceutically acceptable vehicles orcarriers. For administration by injection, it is preferred to use thecompounds in solution in a sterile aqueous vehicle which may alsocontain other solutes such as buffers or preservatives as well assufficient quantities of pharmaceutically acceptable salts or of glucoseto make the solution isotonic.

Suitable vehicles or carriers for the above noted formulations aredescribed in standard pharmaceutical texts, e.g. in “Remington's TheScience and Practice of Pharmacy”, 19th ed., Mack Publishing Company,Easton, Pa., 1995, or in “Pharmaceutical Dosage Forms And Drugs DeliverySystems”, 6th ed., H. C. Ansel et al., Eds., Williams & Wilkins,Baltimore, Md., 1995.

The dosage of the compound will vary with the form of administration andthe particular active agent chosen. Furthermore, it will vary with theparticular host under treatment. Generally, treatment is initiated withsmall increments until the optimum effect under the circumstance isreached. In general, the compound of the present invention is mostdesirably administered at a concentration level that will generallyafford antivirally effective results without causing any harmful ordeleterious side effects. An acceptable amount of the compound of thepresent invention would produce such a concentration level whenadministered to the host under treatment.

For oral administration, the compound or a therapeutically acceptablesalt may be administered in the range of about 0.01 to about 15 mg perkilogram of body weight per day, with a preferred range of about 0.05 toabout 10 mg per kilogram. Alternatively, the compound or atherapeutically acceptable salt may be administered in the range ofabout 0.5 to about 15 mg per kilogram of body weight per day, with apreferred range of about 0.5 to about 5 mg per kilogram

For topical application, the compound of the present invention may beadministered in a suitable formulation to the infected area of the bodye.g. the skin, the genitalia, in an amount sufficient to cover theinfected area. The treatment may be repeated, for example, every four tosix hours until lesions heal.

For parenteral administration, the compound of the present invention maybe administered at a dosage of about 0.01 mg to about 10 mg per kilogramof body weight per day, although the aforementioned variations willoccur. However, a dosage level that is in the range of from about about0.05 mg to about 5 mg per kilogram of body weight per day is mostdesirably employed in order to achieve effective results. Alternatively,the compound of the present invention may be administered at a dosage ofabout 0.1 mg to about 1 mg per kilogram of body weight per day andpreferably at a dosage level of about 0.1 mg to about 0.5 mg perkilogram of body weight per day.

Although the formulations disclosed herein are indicated to be effectiveand relatively safe medications for treating or preventing papillomaviral infections, the possible concurrent administration of theseformulations with other medications or agents to obtain beneficialresults is also contemplated. Such other medications or agents includeTCA, podophyllin, podofilox, Interferon or Imiquimod.

In addition to the above-mentioned antiviral agents, the compoundsaccording to the invention may also be used post-cryotherapy orpost-surgery to avoid recurrence or in combination with any othertreatment for physically removing warts.

Methodology and Synthesis

Numerous methodologies for the preparation of compounds of the presentinvention for use in the treatment or prevention of papilloma virusinfections, will be readily recognized by a person skilled in the art.

The compounds of the present invention can be synthesized as racemicmixtures and then separated into their individual stereoisomers using avariety of routes which will be readily recognized by those skilled inthe art.

In general, the left hand side fragment of the compounds of the presentinvention may be prepared as a nitrile or as an aldehyde bearing the A,R¹ and R² groups as follows:

The A group of the left-hand side fragment is typically introduced ontothe aromatic skeleton of the left-hand side fragment by nucleophilicsubstitution of the halo-substituted aromatic ring (see Example 1below).

The amine intermediate fragment bearing A, R¹, R² and R⁴ groups may beprepared by a variety of routes which will be readily recognized bythose skilled in the art. The general structure of the amineintermediate fragment is as follows:

When the left-hand side fragment is a nitrile, the amine intermediatefragment may be prepared by formation of an intermediate imine complexupon introduction of the R₄ group via nucleophilic attack on thenitrile, followed by reduction of the imine intermediate to the desiredamine product (see Example 7, below). When the left-hand side fragmentis an aldehyde, the intermediate amine fragment may be formed by firstmaking a phosphorylimine which is subsequently reacted with a lithiumanion of the R₄ group to give the phosphorylamine intermediate.Hydrolysis of the latter leads to the desired amine product (see Example9, below).

Coupling of the right-hand side fragment to the amine intermediate maybe achieved by a variety of routes which will be readily recognized bythose skilled in the art. When the invention covers compounds of formula(I) where Y is CH₂ the amine intermediate is coupled to an appropriatecarboxylic acid as follows:

Such coupling will be readily recognized by persons skilled in the art.When the invention covers compounds of the formula (I) where Y is NH,the urea functionality may be achieved by coupling of the amineintermediate to an appropriate right-hand side aniline fragment by avariety of routes which will be readily recognized by those skilled inthe art, including by way of the isocyanate intermediate as follows:

EXAMPLES

The present invention is illustrated in further detail by the followingnon-limiting examples.

Abbreviations or symbols used herein include the following:

-   AcOH: acetic acid;-   DEAD: diethyl azodicarboxylate;-   DIAD: diisopropylazodicarboxylate;-   DIPEA: diisopropylethylamine;-   DMAP: 4-(dimethylamino)pyridine;-   DMSO: dimethylsulfoxide;-   DMF: dimethylformamide;-   ES⁺ MS: electron spray positive mode mass spectrometry;-   Et: ethyl;-   EtOAc: ethyl acetate;-   Et₂O: diethyl ether;-   HATU:    [O-(7-azabenzotriazol-1-yl)-1,2,3,3,tetramethyluroniumhexafluorophosphate];-   HMPA: hexamethyl phosphoramide;-   HPLC: high performance liquid chromatography;-   i-Pr: isopropyl;-   LDA: lithium diisopropylamide;-   Me: methyl;-   MeOH: methanol;-   MeCN: acetonitrile;-   Ph: phenyl;-   RBF: round bottom flask;-   RT: room temperature;-   TBE: tris-borate-EDTA;-   t-Bu; tert-butyl;-   TBTU: 2-(1H-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium    tetrafluoroborate;-   TFA: trifluoroacetic acid;-   THF: tetrahydrofuran;-   TLC: thin layer chromatography.

The present invention is illustrated in further detail by the followingnon-limiting examples.

Left Hand-Side Fragments of Inhibitors

Example 1 Synthesis of 2-methyl-6-piperidin-1-ylbenzonitrile (1b)

2-Methyl-6-piperidin-1-ylbenzonitrile (1 b) was prepared according tothe method described by Grell, W. J. Med. Chem. 1998, 41, 5219. Amixture of 2-chloro-6-methylbenzonitrile (1a, 8.5 g), piperidine (16.6mL, 3 eq) and N-formyl piperidine (12.5 mL) was heated in an oil bath at150° C. under N₂. After a period of 4 days, HPLC indicated completeconversion of starting materials to product. The reaction mixture wascooled to RT, dissolved in 100 mL of EtOAc, washed with water, 10% HCl,and NaHCO₃ (sat), dried over anhydrous MgSO₄ and treated with charcoal.The product was concentrated under vacuum to give the crude product (1b) as pale yellow oil (12.01 g); C₁₈ reversed phase HPLC indicated 88%homogeneity at 220 nm. This crude product was purified by flash columnchromatography (hex-EtOAc, 1:0 to 20:1 to 10:1) to afford2-methyl-6-piperidin-1-ylbenzonitrile (1 b) as colorless oil whichsolidifies upon standing (˜80% yield).

Example 2 Synthesis of 2-piperidin-1-yl-6-thiophen-3-ylbenzonitrile (2c)

A mixture of 2-fluoro-6-iodobenzonitrile (2a, 1.5 g, 6.1 mmol),3-thiopheneboronic acid (0.99 g, 7.7 mmol), LiCl (0.51 g, 12.0 mol),Na₂CO₃ (1.6 g, 15.1 mmol), toluene (10 mL), ethanol (10 mL) and H₂O (7mL) was degassed and de-oxygenated under argon while stirring for 45min. The Pd(Ph₃P)₄ catalyst (0.28 g, 0.24 mmol) was added and themixture was heated to 80° C. for ˜15 hours. The reaction mixture wascooled to RT and the residue was partitioned between H₂O (40 mL) andEtOAc (40 mL). The aqueous layer was extracted two more times with EtOAcand the combined organic layers were dried over anhydrous sodium sulfateand evaporated to dryness under reduced pressure to give compound 2b,which was reacted with piperidine using the procedure described inExample 1. The pure product 2-piperidin-1-yl-6-thiophen-3-ylbenzonitrile(2c) (˜1.2 g, >98% yield) was obtained after flash columnchromatography.

Example 3 Synthesis of 2-methyl-6-piperidin-1-ylbenzaldehyde (3c)

To a solution of the aldehyde 3a (20 g, 161.1 mmol) in dry DMF (160 mL),piperidine (19.1 mL, 193.4 mmol, 1.2 eq) and potassium carbonate (26.73g, 193.4 mmol, 1.2 eq) were successively added. The suspension washeated at 130° C. for 3 h. The reaction mixture was then poured intocold water and acidified with citric acid up to pH 5. The aqueous layerwas extracted 3× with EtOAc and the combined organic extract wassuccessively washed with water, saturated NaHCO₃ and brine. After dryingthe organic extract over MgSO₄, filtration and concentration, thedesired 2-piperidinobenzaldehyde 3b was isolated as a red oil (28.23 g,92% yield).

To a solution of N,N,N′-trimethylethylenediamine in dry THF (110 mL),cooled to −20° C., n-BuLi (27.3 mL of a 1.6 M solution in hexane, 43.68mmol, 1.0 eq) was added dropwise. After 15 min, a solution of2-piperidin-1-ylbenzaldehyde 3b (8.0 g, 42.27 mmol) in THF (20 mL) wasadded slowly while maintaining the temperature at −20° C. After anadditional 15 min, additional n-BuLi (79.25 mL of a 1.6 M solution inhexane, 126.8 mmol, 3.0 eq) was slowly added. The reaction mixture wasmaintained at −20° C. for 90 h using a cryocool apparatus and thencooled to −78° C. for the addition of methyl iodide (15.8 mL, 253.8mmol, 6.0 eq). The cooling bath was removed after the addition and thework-up was carried out once the reaction mixture was at RT. The mixturewas poured into a cold solution of saturated NH₄Cl and extracted 3× withEtOAc. The combined organic layer was washed with brine, dried overanhydrous MgSO₄, filtered and concentrated to afford a brown oil whichwas purified by flash chromatography using a mixture consisting of 5%EtOAc-95% hexane as eluent. The desired2-methyl-6-piperidin-1-ylbenzaldehyde 3c was isolated as pale yellow oil(3.74 g, 43% yield).

Example 4 Synthesis of 2-methyl-6-(4-phenoxypiperidin-1-yl)benzonitrile(4c)

A mixture of the nitrile 4a (1.25 g, 8.25 mmol) and 4-hydroxypiperidine(2.50 g, 24.7 mmol) was heated in a vial to 180° C. for 2 hours. Thereaction mixture was diluted with EtOAc and the organic layer was washedwith 0.1 N HCl, followed by saturated aqueous NaHCO₃ and brine. Theorganic layer was dried over anhydrous MgSO₄ and concentrated todryness. The residue was purified by flash column chromatography, usinga solvent gradient from 20% to 100% EtOAc in hexane, to give the puredesired intermediate alcohol 4b as a white solid (1.44 g).

A sample of the above alcohol intermediate (4b, 153 mg, 0.71 mmol) wasdissolved in anhydrous THF and the solution was cooled to 0° C.Triphenylphosphine (278 mg, 1.1 mmol) and diisopropylazodicarboxylate(DIAD, 209 μL, 1.06 mmol) were added and the mixture was stirred at 0°C. for 10 min before adding phenol (133 mg, 1.4 mmol). The ice bath wasthen removed and the reaction mixture was stirred at RT overnight. TheTHF solvent was first evaporated under vacuum, the residue wasre-dissolved in EtOAc and washed with H₂O, 1N NaOH, H₂O and brine. Theorganic layer was dried over anhydrous MgSO₄ and concentrated todryness. The crude mixture was purified by flash column chromatography,using a solvent gradient from 5% to 20% EtOAc in hexane, to isolate thepure 2-methyl-6-(4-phenoxypiperidin-1-yl)benzonitrile product 4c as awhite solid (180 mg, 87% yield).

Example 5 Synthesis of 2-cyclohexyl-6-methylbenzonitrile (5b)

2-Cyclohexyl-6-methylbenzonitrile was prepared according to the methodof G. Cahiez, F. Lepifre and P. Ramiandrasoa, Synthesis, 1999, No. 12,2138-2144. To a mixture of nitrile 5a (303.2 mg, 2.00 mmol) and MnCl₂tetrahydrate (finely ground, 39.6 mg, 0.2 mmol, 0.1 eq) in dry THF (5mL) at 0° C., the Grignard reagent cyclohexylmagnesium bromide (4 mL,1.0 M solution in THF, 4.0 mmol, 2.0 eq) was added slowly. The reactionmixture was stirred at 0° C. for 2 hours and then quenched by theaddition of a saturated aqueous NH₄Cl solution. The aqueous layer wasextracted with diethyl ether (3×) and the combined organic layers weresuccessively washed with water and brine. After drying over MgSO₄,filtration and concentration, the desired material,2-cyclohexyl-6-methylbenzonitrile 5b, was isolated (168 mg).

Example 6 Synthesis of 2-ethyl-6-piperidin-1-ylbenzonitrile (6b)

In an argon-dried 50 mL 3-neck round bottom flask fitted with a magneticstirring bar, thermometer and septa with argon inlet, anhydrous THF (20mL) and DIPEA (0.84 mL, 6 mmol, 1.2 eq) were introduced consecutively.The mixture was cooled to −30° C. and 1.6 M n-BuLi solution (3.75 mL, 6mmol, 1.2 eq) was added dropwise via syringe. After 30 min stirring at−30° C. the in situ generated LDA solution was cooled to −76° C. andHMPA (1.3 mL, 7.5 mmol, 1.5 eq) was added, followed by a solution of2-methyl-6-piperidinyl-1-ylbenzonitrile (6a, 1.0 g, 5 mmol) in THF (5mL) which caused a dark coloration of the reaction mixture. The reactionwas stirred at C for 2 h and MeI (0.4 mL, 6.5 mmol, 1.3 eq) was added.Immediately the dark brown solution became slightly yellow, indicatingthat the alkylation reaction was complete. The reaction was allowed towarm up to RT, quenched with saturated NH₄Cl solution (20 mL) and theproduct was extracted with diethyl ether (3×30 mL). The combined organicextracts were washed with brine, dried over anhydrous sodium sulfate andthe solvent was removed under reduced pressure. The crude product waspurified by flash chromatography (eluted with 5% EtOAc in hexane) togive pure 2-ethyl-6-piperidin-1-ylbenzonitrile (6b, 0.88 g, 82% yield).

Amine Intermediate Fragment of Inhibitors

Example 7 Synthesis of1-(2-methyl-6-piperidin-1-yl-phenyl)-1-phenyl-methylamine (7c)

A solution of bromobenzene (118 mg, 0.75 mmol) in dry THF (2 mL) wascooled to −78° C. and n-BuLi (1.6 M in hexane, 0.375 mL, 0.6 mmol) wasadded. The reaction mixture was stirred for 30 min at −78° C., then asolution of nitrile 1b (100 mg, 0.5 mmol, in 1 mL of THF) was added andstirring was continued at −78° C. for 5 more min. The reaction mixturewas allowed to warm up to RT and stirring was continued for 2 hours. Thereaction was quenched with the addition of saturated NH₄Cl (1.5 mL) andNH₄OH (1.5 mL) followed by stirring for 30 min. The organic layer wasseparated, the aqueous layer was re-extracted with EtOAc and thecombined organic layers were washed with brine, dried over anhydrousMgSO₄ and concentrated under vacuum to give the crude imine intermediate7b which was used in the next step without purification.

The crude imine intermediate 7b was re-dissolved in THF (3 mL), BH₃.SMe₂(10M, 100 μL, 1.0 mmol) was added and the reaction mixture was heated toreflux for 6 hours. The solvent was removed under vacuum, the cruderesidue was acidified with 3 mL of 1N HCl and washed with EtOAc (2×10mL). The pH of the aqueous layer was adjusted to 8-10 by addition of 10NNaOH and the product was extracted into EtOAc (2×10 mL). The combinedorganic layers were washed with brine, dried over MgSO₄ and evaporatedto dryness to give a pale yellow oil. This crude product was purified byflash column chromatography (using a gradient from hexane-EtOAc 10:1 to5:1 then CH₂Cl₂-MeOH 1:0 to 10:1) to provide 7c as a racemic mixture.The yield varied from 35-70%. ES⁺ MS m/z: 281 (M+H)⁺

Example 8 Synthesis of1-(4-methoxyphenyl)-1-(2-methyl-6-piperidin-1-ylphenyl)methylamine (8c)

A dry 25 mL 3-neck flask with a stirring bar and condenser was flushedwith argon. A solution of nitrile 1b (0.33 g, 1.43 mmol) in toluene (10mL) was added and the volume of the solution was reduced to ˜1/5 bydistilling out some of the toluene. The solution was cooled to RT andthe Grignard reagent 4-methoxyphenyl-magnesium bromide (5.75 mL, 0.5 Min THF) was added. The reaction mixture was heated to reflux and the THFwas first removed by distillation before leaving the mixture to reflux,while stirring, for approximately 15 hours. The reaction was cooled backto RT, BH₃.SMe₂ (1.0 M, 3 mL) was added and the mixture was heated toreflux for 15 hours. The solvent was removed under vacuum, 10% aqueousHCl was added (20 mL) and the mixture was heated again to reflux for 2.5hours. The reaction mixture was first extracted with diethyl ether (2×10mL), the aqueous layer was neutralized with NH₄OH and extracted withEtOAc (3×15 mL). The EtOAc layer was dried over anhydrous MgSO₄ andevaporated to dryness. The residue was purified by flash columnchromatography, using 1-2% CH₃OH in CH₂Cl₂, to give the racemic products1-(4-methoxy-phenyl)-1-(2-methyl-6-piperidin-1-yl-phenyl)-methylamine 8cas a yellow oil (0.44 g, 90% yield).

Chiral HPLC was utilized to afford the enantiomerically-enrichedsamples. Separation of the two enantiomers was achieved by preparativescale HPLC, using a ChiralCel OD column (2.00 cm×25 cm), 40% aqueousCH₃CN (containing 0.06% TFA) as eluting solvent at a flow rate of 7ml/min. The enantiomer of the first eluting amine had an e.e. value of98.8% as determined by analytical chiral HPLC, and was used tosynthesize potent inhibitors of HPV (eutomer). Compounds synthesizedwith the enantiomer corresponding to the second eluting peak weresignificantly less active as inhibitors of HPV (distomer).

Example 9 Synthesis of1-(2-Methyl-6-piperidinylphenyl)-1-[4-(2-pyrrolidin-1-ylethoxy)phenyl]methylamine(9d)

To a solution of aldehyde 3c (1.17 g, 4.92 mmol), diphenylphosphinamide(1.068 g, 4.92 mmol, 1.0 eq), and triethylamine (2.07 mL, 14.84 mmol,3.0 eq) in dry CH₂Cl₂ (6 mL) at 0° C. was added dropwise a 1.0 M TiCl₄solution in dichloromethane (2.68 mL, 2.68 mmol). The mixture wasstirred for 10 min. at 0° C. and then overnight at RT. The heterogeneousmixture was filtered through a pad of Celite. The filtrate wasconcentrated and the residue was treated twice with ether, and thetriethylammonium hydrochloride salt that precipitated each time wasremoved by filtration. After concentration the desired imine 9b wasisolated as a yellow oil (1.532 g, 3.80 mmol, 77% yield). The desiredimine showed a characteristic doublet of ˜32 Hz coupling constantbetween the imine C—H and P.

To 1-[2-(4-bromophenoxy)ethyl]pyrrolidine (41.4 μL, 0.2 mmol, 2.0 eq) indry THF (500 μL) at −78° C. was slowly added n-BuLi (230 μL, 0.368 mmol,1.8 eq). After 1 h the crude imine 9b (40.2 mg, 0.10 mmol) in THF (250μL) was added. After the addition was completed, the reaction mixturewas allowed to warm-up to RT and stirred at this temperature for 15 min.A saturated aqueous solution of NH₄Cl was added (600 μL) and the aqueouslayer was extracted with EtOAc (3×). The combined organic extract waswashed with brine, dried over MgSO₄, filtered and concentrated to givethe crude protected amine 9c. This crude intermediate was dissolved inabsolute methanol (500 μL) and a solution of 4N HCl in dioxane (500 μL)was added. The reaction mixture was stirred at RT overnight andconcentrated to dryness to give the desired hydrochloride salt of1-(2-methyl-6-piperidinylphenyl)-1-[4-(2-pyrrolidin-1-ylethoxy)phenyl]methylamine9d, which was used in the synthesis of inhibitors without furtherpurification.

Right-Hand Side Fragments of Inhibitors where X₂═CH

Example 10 Synthesis of methyl 5-bromo-4-carboxymethyl-2-methoxybenzoate(10d)

Methyl 5-bromo-4-carboxymethyl-2-methoxybenzoate was synthesizedaccording to the method described in WO 01/35900. A 1 L 3-neck RBF,fitted with a dropping funnel, a condenser and a magnetic stirring barwas charged with 4-methylsalicylic acid 10a (50 g, 0.33 mol), K₂CO₃(91.1 g, 0.66 mol, 2 eq) and dry acetone (500 mL). This mixture washeated under reflux while dimethylsulfate (112.3 g, 0.891 mol, 2.7 eq)was added dropwise. The reaction mixture was refluxed for ˜14 h (TLCindicated that the reaction was completed). The inorganic salts werefiltered off and the THF filtrate was evaporated under reduced pressureto obtain a yellow oil. This residue was dissolved in 400 mL MeOH and asolution of conc. NH₄OH (115 mL) was added. The resulting mixture wasstirred at RT for 30 min. The MeOH was then distilled off and theresidue was diluted with water (500 mL) and the oily product wasextracted with diethyl ether (3×300 mL). The combined organic extractswere dried over sodium sulfate and the diethyl ether was removed undervacuum to give pure methyl 2-methoxy-4-methylbenzoate 10b as a yellowoil (57 g, 96% yield).

A dry 2 L 3-neck RBF fitted with an argon inlet, a thermometer, amagnetic stirring bar and a septum was charged with THF (220 mL) anddiisopropylamine (54.6 mL, 0.39 mol, 1.2 eq). The resulting mixture wascooled to −50° C. and a solution of 2.5 M n-BuLi (156 mL, 0.39 mol, 1.2eq) was added slowly via cannula. After 30 min of stirring at −50° C.,the solution of LDA generated was cooled to −78° C. and HMPA (67.8 mL,0.39 mol, 1.2 eq) was added, followed by a solution of methyl2-methoxy-4-methylbenzoate 10b (57 g, 0.32 mol) in THF (220 mL), whilemaintaining the temperature at −78° C. The reaction mixture was stirredtwo more hours at −78° C., and then cannulated into a flask containing100 g dry ice and THF (200 mL). After 30 min stirring at −78° C., thereaction mixture was allowed to warm up slowly to RT and then pouredinto water (1.5 L). The organic layer was separated and the aqueouslayer was further extracted with ether (3×1 L). The water layer wasacidified with a solution of 10% H₂SO₄ (150 mL) and the reaction productwas extracted into CH₂Cl₂ (3×1.5 L). The combined organic extracts weredried over anhydrous Na₂SO₄, the solvent was removed under reducedpressure and the crude product was purified by flash chromatography(eluent EtOAc: hexane 3:7), followed by recrystallization fromCH₂Cl₂:hexane 1:1 to afford pure methyl4-carboxymethyl-2-methoxybenzoate 10c (38.8 g, 54.7% yield).

Methyl 4-carboxymethyl-2-methoxybenzoate 10c (12.7 g, 0.0567 mol) wasdissolved in glacial AcOH (100 mL) and bromine (3.2 mL, 0.0624 mol, 1.1eq) was added drop wise via a syringe, while maintaining the internaltemperature between 20-25° C. After stirring for 4 h at RT, the AcOH wasevaporated and the orange oil co-evaporated twice with toluene to givean orange solid. This material was triturated with CH₂Cl₂ and some ofthe precipitated product was removed by filtration. The rest of theproduct which remained in the filtrate was then concentrated, loaded ona silica gel column and eluted with 1% AcOH in EtOAc:hexane (6:4 ratio).The product was further purified by a second chromatography andre-crystallization from EtOAc:hexane to give pure methyl5-bromo-4-carboxymethyl-2-methoxybenzoate as white solid 10d (totalamount 9 g, 52% yield).

Example 11 Synthesis of methyl 4-carboxymethylnaphthalene-1-carboxylate(11c)

Synthesis of intermediate 4-carboxymethylnaphthalene-1-carboxylic acidmethyl ester 11c was carried out following the same experimentalprocedures as those previously described for the synthesis of theintermediate methyl 4-carboxymethyl-2-methoxybenzoate in Example 10.

Example 12 Synthesis of (2-bromo-5-methoxy-4-sulfamoylphenyl)acetic acid(12f)

A 250 ml 3-neck RBF fitted with a magnetic stirring bar, a thermometerand a dropping funnel was charged with methyl 2-methoxy-4-methylbenzoate10b (10 g, 0.056 mol) and AcOH (70 mL). To this solution bromine (3 mL,0.06 mol) was added drop-wise while maintaining the reaction temperaturebelow 25° C. When bromine addition was complete, the reaction mixturewas stirred at RT for 2 hours, then poured into 600 mL of cold water andthe pH was adjusted to 8-9 with Na₂CO₃. The crude product was extractedwith Et₂O (3×300 mL), the combined extracts washed with brine, driedover sodium sulfate and the solvent was removed under vacuum to givemethyl 5-bromo-2-methoxy-4-methylbenzoate as an orange oil, whichsolidified on standing (14.3 g, 99% yield, >90% purity by ¹H NMR).

Methyl 5-bromo-2-methoxy-4-methylbenzoate (11.64 g, 0.045 mol) wasdissolved in a mixture of EtOH:H₂O (1:1 ratio, 150 mL), NaOH (5.8 g,0.145 mol) was added and reaction mixture was refluxed for 30 min. TheEtOH solvent was removed from the mixture by distillation which leads toprecipitation of the desired product as its sodium salt. The residue wasdiluted with H₂O (75 mL) and the pH was adjusted to 2 with concentratedHCl. The precipitate was collected by filtration, washed with H₂O (3×50mL) and air dried to give pure 5-bromo-2-methoxy-4-methylbenzoic acid12a (9 g, 82% yield) as a beige solid.

A mixture of 5-bromo-2-methoxy-4-methylbenzoic acid 12a (9 g, 0.037mol), thionyl chloride (5 ml, 0.069 mol) and benzene (90 mL) was heatedto reflux for 4 hours, then evaporated to dryness at reduced pressure.The residue of the chloroanhydride intermediate was dissolved in drybenzene (40 mL) and poured slowly into an ice cooled flask containing150 mL of concentrated ammonium hydroxide solution. The reaction mixturewas then stirred for 1 hour at RT and the solid material whichprecipitated was collected by filtration, washed with water (3×25 mL),benzene (2×20 mL) and air dried to afford pure5-bromo-2-methoxy-4-methylbenzamide 12b (8.5 g, 95% yield) as beigesolid.

A 250 ml 3-neck RBF fitted with a magnetic stirring bar, a thermometer,a dropping funnel and a condenser was charged with5-bromo-2-methoxy-4-methylbenzamide 12b (6 g, 24.6 mmol), anhydrous MeOH(40 mL) and 25% NaOMe solution in MeOH (21 mL, 98.4 mmol). This slurrywas cooled to 5° C. and bromine (1.4 mL, 27.1 mmol) was added drop wisecausing an exothermic reaction and the formation of a cloudy solution.The reaction mixture was stirred for 30 min at RT, and then heated toreflux for 1 hour. The solvent was removed under vacuum, the residue wasre-dissolved in EtOH (50 mL) and KOH (5.5 g, 98.4 mmol) was added. Themixture was allowed to react under reflux for 16 hours in order tohydrolyze the intermediate methylcarbamate. Then the reaction mixturewas diluted with H₂O (300 mL) and the product was extracted into Et₂O(3×100 mL). The combined organic layers were filtered through a pad ofsilica gel and evaporated to dryness to give5-bromo-2-methoxy-4-methylaniline 12c (4.8 g, 90% yield) pure by ¹H NMRas a light brown solid.

A suspension of 5-bromo-2-methoxy-4-methylaniline hydrochloride [formedfrom the reaction of 5-bromo-2-methoxy-4-methylaniline (4.32 g, 20 mmol)with conc. HCl (20 ml)] was cooled to 0° C. and an aqueous solution ofNaNO₂ (1.224 g, 24 mmol in 5 mL H₂O) was added slowly, keeping thereaction temperature below 5° C. When addition of the nitrite wascomplete, the reaction mixture was stirred for 30 min at 0° C., thenpoured into a previously prepared mixture containing 30% SO₂ in AcOH (30mL), a solution of CuCl₂.2H₂O (5.13 g, 30 mmol) in 15 mL H₂O and benzene(20 mL). The reaction mixture was heated slowly to 35° C., at whichpoint the evolution of nitrogen gas was observed. When gas evolution hadstopped, the reaction mixture was diluted with water (200 mL), theorganic layer was separated, washed with an aqueous solution ofsaturated NaHCO₃, dried over Na₂SO₄ and evaporated to dryness to givethe crude sulfonylchloride 12d as a brown oil (˜3 g). This intermediatewas dissolved in hexane (20 mL), a solution of concentrated NH₄OH (20mL) was added and reaction mixture was stirred vigorously at RTovernight. The brown solid formed was collected by filtration andtreated with 10% KOH solution (20 mL). Any insoluble impurities wereremoved by filtration and the filtrate was acidified to give a beigeprecipitate which was filtered, washed with water and air dried to givethe pure product 5-bromo-2-methoxy-4-methylbenzenesulfonamide 12e (0.586g, 10.4% overall yield).

A dry 25 mL 3-neck RBF, fitted with a magnetic stirring bar, athermometer and septum with Ar inlet was charged with5-bromo-2-methoxy-4-methylbenzene-sulfonamide 12e (0.586 g, 2.1 mmol),anhydrous THF (5 mL) and HMPA (0.37 mL, 2.1 mmol). The mixture wascooled to −75° C. and a 2.0 M solution of LDA (4.2 mL, 8.4 mmol) wasadded drop wise via a syringe. The reaction mixture was stirred at −75°C. for 1.5 hours and then cannulated into a flask containing 20 g of dryice and 5 mL THF and left to warm up slowly to RT. The solvent wasremoved under reduced pressure and H₂O (20 mL) was added to the residue.At this point, some of the unreacted starting material precipitated andwas removed by filtration. The filtrate was acidified and the solutionwas extracted with EtOAc (3×20 mL). The combined organic layers wereevaporated to dryness, the residue was treated with an aqueous solutionof saturated NaHCO₃ (10 mL) and the insoluble material was separated byfiltration. The filtrate was acidified with concentrated HCl and thecloudy solution extracted again with EtOAc (3×5 mL). The combinedorganic layers were concentrated to ˜1 mL, causing crystallization ofthe product, which was collected by filtration to give pure(2-bromo-5-methoxy-4-sulfamoylphenyl)acetic acid (20 mg) 12f (˜3%yield).

Synthesis of Inhibitors

Example 132-(2-Bromo-5-methoxy-4-sulfamoylphenyl)-N-[1-(4-methoxy-phenyl)-1-(2-methyl-6-piperidin-1-ylphenyl)methyl]acetamide(301)

A reaction mixture containing(2-bromo-5-methoxy-4-sulfamoylphenyl)acetic acid 12f from Example 12 (18mg, 0.06 mmol),1-(4-methoxyphenyl)-1-(2-methyl-6-piperidin-1-ylphenyl)methylamine 8cfrom Example 8 (25.9 mg, 0.08 mmol), HATU (45.6 mg, 0.12 mmol) and DIPEA(0.06 ml, 0.3 mmol) in a solvent mixture of THF (1 mL) and DMF (0.3 mL)was stirred under argon at RT for 1 hour. The mixture was then dilutedwith EtOAc (7 mL) and the organic layer was washed with 1.0 M aqueousHCl (2 mL), saturated NaHCO₃ (2 mL), dried over Na₂SO₄, concentrated toa minimum volume (˜1 mL) and purified by preparative TLC (eluentEtOAc:hexane:AcOH 60:40:1) to obtain 31 mg of the semi-pure finalinhibitor (˜85% purity by ¹H-NMR). The pure inhibitor2-(2-bromo-5-methoxy-4-sulfamoylphenyl)-N-[1-(4-methoxyphenyl)-1-(2-methyl-6-piperidin-1-ylphenyl)methyl]acetamide301 (Table 3) was isolated after further purification by C₁₈ reversedphase HPLC.

¹H NMR (400 MHz, DMSO, 325 K) δ: 1.2-1.6 (m, 4H, piperidine ring), 2.20(s, 3H, —CH3), 2.5-2.8 m (2H, piperidine ring), 3.71 (s, 3H, —OCH₃),3.85 (s, 3H, —OCH₃), 3.8-4.0 (m, 2H, —CO—CH₂—), 6.83 (d, J=8.3 Hz, 2H),6.97 (br d, J=8.3 Hz, 2H), 7.1-7.2 (m, 4H), 7.30 (s, 1H), 7.83 (s, 1H),8.36 (br s, NH).

ES⁺ MS m/z: 616.2 and 618.2 (M+H)⁺.

Example 145-Chloro-2-methoxy-4-{3-[(2-methyl-6-piperidin-1-yl-phenyl)(phenyl)methyl]ureido}benzoicacid (201)

Methyl 4-amino-5-chloro-2-methoxybenzoate 14b (19.4 mg, 0.09 mmol),prepared from the commercially-available acid by standard esterificationmethods, was dissolved in dichloromethane (0.5 mL) and cooled to 0° C.for the successive addition of DIPEA (0.1 mL, 0.57 mmol) and phosgene(20% in toluene, 0.2 mL, 0.40 mmol). The reaction mixture was stirredfor 2 h at RT and then concentrated under reduced pressure. The residuewas dissolved in dichloromethane (0.5 mL) and then successively treatedwith DIPEA (0.1 mL, 0.57 mmol) and the intermediate amine 7c fromExample 7 (25 mg, 0.089 mmol). The reaction mixture was stirred for 2 hat RT and then concentrated under vacuum. An aqueous solution of 5%KHSO₄ was added and the mixture was extracted with EtOAc. The organiclayer was washed with brine and dried over anhydrous MgSO₄. Afterfiltration and concentration the residue was dissolved in a mixture ofTHF (0.1 mL), methanol (0.2 mL) and water (0.2 mL) and then a 10 Naqueous NaOH solution (0.1 mL, 1.0 mmol) was added. The reaction mixturewas stirred overnight at RT and then concentrated to dryness. Theresidue was dissolved in glacial acetic acid and purified by reversedphase HPLC to afford the desired compound5-chloro-2-methoxy-4-{3-[(2-methyl-6-piperidin-1-ylphenyl)(phenyl)methyl]ureido}benzoicacid 201 (Table 2) as its TFA salt (23 mg, 48% yield).

¹H NMR (400 MHz, DMSO, 325 K) δ: 1.5-1.7 (m, 4H, piperidine ring), 2.02(s, 3H, —CH₃), 2.8-2.9 m (2H, piperidine ring), 3.76 (s, 3H, —OCH₃),6.94 (d, J=7.3 Hz, 1H), 7.08 (2d, J=7.6 Hz, 2H), 7.16-7.22 (m, 3H), 7.29(dd, J=7.6 Hz, 1H), 7.7 (s, 1H), 7.70 (br, ˜1H, NH), 8.16 (s, 1H), 8.64(br, ˜1H, NH).

ES⁺ MS m/z: 509.3 (M+H)⁺

Example 15 Determination of the Absolute Configuration of the HPV E1-E2Interaction Inhibitor (105)

The racemic amine fragment precursor 15 (this amine fragment wasprepared using methods analogous to those described in Examples 1 and 8)was separated into its two enantiomers 15a and 15b by chiral HPLC andthe two enantiomerically enriched amines were coupled independently tocamphor sulphonyl chloride to obtain compounds 15c and 15d; the lattercompound produced high quality crystals for x-ray crystallography. Forcorrelation purposes, the two enantiomerically-enriched samples (15a and15b) were also coupled to a right-hand side carboxylic acid fragment toproduce one potent inhibitor (the eutomer 15e) and the distomer (15f).X-ray crystallography of the sulfonamide 15d allowed assignment of thiscompound to the R-configuration at the previously unknown chiral center.The same amine precursor (15b) was also used to make the distomer 15f.In contrast the eutomer 15e (compound 105, Table 1) which was made fromthe S chiral amine 15a, was found to be a potent inhibitor in the HPV 11E1-E2 DNA assay.

Example 16 E2-Dependent E1 DNA Binding Assay

The protocol for the E2-dependent E1 DNA binding assay is described indetail in WO 02/50082.

Example 17 SV40 T Antigen-DNA Binding Assay

The protocol for the SV40 T antigen DNA binding assay is described indetail in WO 02/50082.

Example 18 Cell-Based DNA Replication Assay

The protocol for the cell-based DNA replication assay is described indetail in WO 02/50082.

Example 19 Tables of Compounds

All compounds listed in Tables 1-4 were found to be active in the E1-E2DNA assay referred to in Example 16 with an IC₅₀ value under 20 μM forHPV-11.

Certain compounds were also tested in the SV40 TAg assay of Example 17and were found to be inactive or less active than in the E1-E2 DNAassay, providing good evidence that these compounds are selectiveagainst the papilloma virus.

In addition, at least one compound was tested in the DNA replicationcellular assay of Example 18. The results obtained indicate that thesecompounds may be able to inhibit viral DNA replication. TABLE 1

MS Cpd R¹ R² A R^(4*) Y R⁵ R⁶ (M+H)^(*) 101 Me H

Ph CH₂ OMe H 473.6 102 Me H

Ph CH₂ OMe H 475.6 103 Me H

Ph NH OMe H 474.6 104 Me H

CH₂ OMe H 503.6 105 Me H

Ph (enantiomerically enriched) CH₂ OMe H 475.6 106 Me H

—(CH₂)₃—CH₃ CH₂ OMe Br 531.3 107 Me H

CH₂ OMe Br 557.2 108 Me H

CH₂ OMe Br 557.2 109 Me H

CH₂ OMe Br 542.5 110 H 1-F

CH₂ OMe Br 585.2 111 H H

CH₂ OMe Br 569.2 112 Me H

CH₂ OMe Br 559.2 113 Et H

CH₂ OMe Br 597.1 114 Me H

Me CH₂ OMe Br 491.2 115 Me H

iPr CH₂ OMe Br 519.2 116 Me H

CH₂ OMe Br 581.5 117 Me H

CH₂ OMe Br 575.4 118 Me H

CH₂ OMe Br 597.2 119 Me H

CH₂ OMe Br 611.2 120 Me H

CH₂ OMe Br 597.2 121 Me H

CH₂ OMe Br 603.2 122 Me H

CH₂ OMe Br 633.2 123 Me H

CH₂ OMe Br 617.3 124 Me H

CH₂ OMe Br 597.2 125 Me H

CH₂ OMe Br 675.1 126 Me H

CH₂ OMe Br 619.1 127

H

Me CH₂ OMe Br 559.2 128 Me H

CH₂ OEt H 522.1 129 Me H

Ph (enantiomerically enriched) CH₂ OEt H 487.6*All compounds are racemic unless otherwise indicated.

TABLE 2

MS Cpd * R⁴⁰ R⁴¹ R⁴² R⁴³ R⁴⁴ Y R⁶ (M+H)^(*) 201 — H H H H H NH Cl 509.3202 — H H H H H NH Br 553.5 203 enantiome H H OMe H H CH₂ Br 581.2rically enriched 204 — H H H H OMe CH₂ Br 581.2 205 — H H H H Me CH₂ Br565.2 206 — H H Me H Me CH₂ Br 579.2 207 — H H H OMe H CH₂ Br 581.2 208— H H H —CH₃ H CH₂ Br 565.2 209 — H H

H H CH₂ Br 594.3 210 — H H SMe H H CH₂ Br 597.2 211 — H H t-Bu H H CH₂Br 607.3 212 — H H CF₃ H H CH₂ Br 619.2 213 — H H Cl H H CH₂ Br 585.2214 — H H

H H CH₂ Br 664.3 215 — H H OMe H OMe CH₂ Br 611.3 216 — OMe H OMe H OMeCH₂ Br 641.3 217 — H H H H iPr CH₂ Br 593.3 218 — H Me OMe H H CH₂ Br541.2 219 — H H H H H CH₂ Br 552.2 220 — H H Ph H H CH₂ Br 647.2*All compounds are racemic unless otherwise indicated.

TABLE 3

All compounds are racemic unless otherwise indicated. MS Cpd R¹ A R⁴ YR⁵ CR⁶—X₂ R^(c) (M+H)^(*) 301 Me

CH₂ OMe CBr—CH SO₂NH₂ 618.2 302 Me

CH₂ H

COOH 523.3

TABLE 4 (VI)

All compounds are racemic unless otherwise indicated. MS Cpd R¹ A R⁴ Y ZX₃ R^(c) M(+H)^(*) 401 Me

NH S S COOH 496.2

1. A compound of formula (I) or its enantiomers or diastereoisomersthereof:

wherein R¹ is H, (C₁₋₆)alkyl, halo, (C₁₋₆)haloalkyl, (C₁₋₆)alkoxy,(C₁₋₆)alkylthio, amino, (C₁₋₆)alkylamino, di((C₁₋₆)alkyl)amino,(C₃₋₇)cycloalkyl, phenyl, or 5- or 6-membered heterocycle; X₁ is CR² orN; one or both free positions on the phenyl ring may be substituted withR² and each R² is independently selected from: H, (C₁₋₆)alkyl, halo,(C₁₋₆)haloalkyl, (C₁₋₆)alkoxy, (C₁₋₆)alkylthio, amino, (C₁₋₆)alkylaminoand di((C₁₋₆)alkyl)amino; A is (C₃₋₇)cycloalkyl, aryl or heterocycle,each of which being optionally substituted with one or more substituentsindependently selected from: (C₁₋₆)alkyl, halo, (C₁₋₆)haloalkyl,(C₁₋₆)alkoxy, (C₁₋₆)alkylthio, amino, (C₁₋₆)alkylamino, ordi((C₁₋₆)alkyl)amino, aryl, O-aryl, S-aryl, NH-aryl, (C₁₋₆)alkyl-aryl,heteroaryl, O-heteroaryl, S-heteroaryl, NH-heteroaryl and(C₁₋₆)alkyl-heteroaryl; or A is NHR³ or N(R³)₂ wherein each R³ isindependently selected from H, (C₁₋₆)alkyl, (C₃₋₇)cycloalkyl, aryl andheteroaryl; R⁴ is (C₁₋₆)alkyl, (C₃₋₇)cycloalkyl, aryl, heterocycle,(C₁₋₆)alkyl-aryl or (C₁₋₆)alkyl-heterocycle, each of which beingoptionally substituted with one or more substituents independentlyselected from: (C₁₋₆)alkyl, halo, (C₁₋₆)haloalkyl, (C₁₋₆)alkylthio,amino, (C₁₋₆)alkylamino, di((C₁₋₆)alkyl)amino, aryl, heteroaryl,(C₁₋₆)alkyl-aryl, (C₁₋₆)alkyl-heteroaryl, and (C₁₋₆)alkoxy, wherein said(C₁₋₆)alkoxy is optionally substituted with aryl or heteroaryl; or R⁴ isphenyl fused with a saturated or unsaturated 4- to 6-membered ringoptionally containing one to three heteroatoms independently selectedfrom N, O, and S; Z is O or S; Y is CH₂, NH or O; B is selected from:

 wherein R⁵ is H, (C₁₋₆)alkyl, (C₃₋₇)cycloalkyl, halo, (C₁₋₆)haloalkyl,(C₁₋₆)alkoxy, (C₁₋₆)alkylthio, amino, (C₁₋₆)alkylamino,di((C₁₋₆)alkyl)amino, hydroxyl or sulfhydryl; X₂ is CR⁷ or N; R⁶ and R⁷are independently H, (C₁₋₆)alkyl, halo, (C₁₋₆)haloalkyl, (C₁₋₆)alkoxy,(C₁₋₆)alkylthio, amino, (C₁₋₆)alkylamino, di((C₁₋₆)alkyl)amino, hydroxylor sulfhydryl; or, when X₂ is CR⁷, R⁶ and R⁷ are optionally bondedtogether to form a saturated or unsaturated 5- or 6-membered ringoptionally containing one or two heteroatoms independently selected fromS, O and N; X₃ is O, S or NR⁸, wherein R⁸ is H or (C₁₋₆)alkyl; and R^(c)is COOH, CONHR⁹, SO₂NHR⁹, CONHSO₂R⁹, CONHSO₂NHR⁹, triazolyl ortetrazolyl, wherein R⁹ is H, (C₁₋₆)alkyl, (C₃₋₆)cycloalkyl or phenyl;provided that R⁵ and R⁶ cannot both together be H and when R⁵ or R⁶ isH, then R¹ is not H, and provided that when Y is NH, R⁶ cannot behydroxyl or sulfhydryl; or a pharmaceutically-acceptable salt or esterthereof.
 2. The compound according to claim 1 wherein R¹ is H,(C₁₋₆)alkyl, halo, (C₁₋₆)haloalkyl, (C₁₋₆)alkoxy, (C₁₋₆)alkylthio,amino, (C₁₋₆)alkylamino, di((C₁₋₆)alkyl)amino, (C₃₋₇)cycloalkyl, phenyl,or 5- or 6-membered heterocycle; X₁ is CR² or N; each R² isindependently selected from: H, (C₁₋₆)alkyl, halo, (C₁₋₆)haloalkyl,(C₁₋₆)alkoxy, (C₁₋₆)alkylthio, amino, (C₁₋₆)alkylamino ordi((C₁₋₆)alkyl)amino; A is (C₃₋₇)cycloalkyl, (C₆ or C₁₀)aryl orheterocycle, all of which being optionally substituted with:(C₁₋₆)alkyl, halo, (C₁₋₆)haloalkyl, (C₁₋₆)alkoxy, (C₁₋₆)alkylthio,amino, (C₁₋₆)alkylamino, or di((C₁₋₆)alkyl)amino, aryl, O-aryl, S-aryl,NH-aryl, (C₁₋₆)alkyl-aryl, heteroaryl, O-heteroaryl, S-heteroaryl,NH-heteroaryl or (C₁₋₆)alkyl-heteroaryl; or A is NHR³ or N(R³)₂ whereinR³ is independently selected from H, (C₁₋₆)alkyl, (C₃₋₇)cycloalkyl, aryland heteroaryl; R⁴ is (C₁₋₆)alkyl, (C₃₋₇)cycloalkyl, (C₆ or C₁₀)aryl,heterocycle, (C₁₋₆)alkyl-aryl or (C₁₋₆)alkyl-heterocycle, all of whichbeing optionally substituted with: (C₁₋₆)alkyl, halo, (C₁₋₆)haloalkyl,(C₁₋₆)alkoxy, (C₁₋₆)alkylthio, amino, (C₁₋₆)alkylamino,di((C₁₋₆)alkyl)amino, aryl, heteroaryl, (C₁₋₆)alkyl-aryl,(C₁₋₆)alkyl-heteroaryl, (C₁₋₆)alkoxy-aryl or (C₁₋₆)alkoxy-heteroaryl; orwherein the (C₆)aryl is fused with a saturated or unsaturated 4- to6-membered ring optionally containing one to three heteroatoms selectedfrom N, O, and S; Z is O or S; Y is CH₂, NH or O; B is selected from:

 wherein R⁵ is H, (C₁₋₆)alkyl, (C₃₋₇)cycloalkyl, halo, (C₁₋₆)haloalkyl,(C₁₋₆)alkoxy, (C₁₋₆)alkylthio, amino, (C₁₋₆)alkylamino,di((C₁₋₆)alkyl)amino, hydroxyl or sulfhydryl; X₂ is CR⁷ or N; R⁶ and R⁷are independently H, (C₁₋₆)alkyl, halo, (C₁₋₆)haloalkyl, (C₁₋₆)alkoxy,(C₁₋₆)alkylthio, amino, (C₁₋₆)alkylamino, di((C₁₋₆)alkyl)amino, hydroxylor sulfhydryl; or, when X₂ is CR⁷, R⁶ and R¹ are optionally bondedtogether to form a saturated or unsaturated 5- or 6-membered ringoptionally containing one or two heteroatoms selected from S, O and N;X₃ is O, S or NR⁸, wherein R⁸ is H or (C₁₋₆)alkyl; and R^(c) is COOH,CONHR⁹, SO₂NHR⁹, or tetrazolyl, wherein R⁹ is H, (C₁₋₆)alkyl,(C₃₋₆)cycloalkyl or phenyl; provided that R⁵ and R⁶ cannot both togetherbe H and when R⁵ or R⁶ is H, then R¹ is not H, and provided that when Yis NH, R⁶ cannot be hydroxyl or sulfhydryl; or apharmaceutically-acceptable salt or ester thereof.
 3. The compoundaccording to claim 1 wherein R¹ is methyl or ethyl.
 4. The compoundaccording to claim 1 wherein A is cyclohexyl, phenyl, 1-piperidinyl,4-morpholinyl, N(H)cyclohexyl, or N(CH₃)cyclohexyl, said cyclohexyl,phenyl, 1-piperidinyl and 4-morpholinyl being optionally mono- ordi-substituted with: (C₁₋₆)alkyl, halo, (C₁₋₆)haloalkyl or phenoxy. 5.The compound according to claim 4 wherein A is 1-piperidinyl optionallymono- or di-substituted with halo or phenoxy, and R¹ is H or(C₁₋₆)alkyl.
 6. The compound according to claim 1 wherein R⁴ is thienyl,furanyl or naphthyl optionally substituted with one or more substituentsindependently selected from methoxy and (C₁₋₆)alkyl.
 7. The compoundaccording to claim 1 wherein R⁴ is phenyl, optionally substituted withone to four substituents independently selected from: methoxy, halo, andphenyl, or R⁴ is phenyl fused with a saturated or unsaturated 4- to6-membered ring optionally containing one to three heteroatomsindependently selected from N, O, and S.
 8. The compound according toclaim 1 wherein R⁵ is methoxy or ethoxy.
 9. The compound according toclaim 1 wherein R⁶ is alkyl or halo.
 10. The compound according to claim1 wherein X₂ is CR⁷, wherein R⁷ and R⁶ are bonded together to form anunsaturated 6-membered ring which optionally contains one or twoheteroatoms independently selected from S, O and N.
 11. The compoundaccording to claim 1 wherein R¹ is H, (C₁₋₆)alkyl, halo,(C₁₋₆)haloalkyl, (C₁₋₆)alkoxy, (C₁₋₆)alkylthio, amino, (C₁₋₆)alkylamino,or di((C₁₋₆)alkyl)amino; X₁ is CR² or N; each R² is independentlyselected from: H or halo; A is (C₃₋₇)cycloalkyl, phenyl, or a 5- or6-membered monocyclic heterocycle, each of which being optionallysubstituted with one or more substituents independently selected from:(C₁₋₆)alkyl, halo, (C₁₋₆)haloalkyl, (C₁₋₆)alkoxy, (C₁₋₆)alkylthio,amino, (C₁₋₆)alkylamino, di((C₁₋₆)alkyl)amino and aryloxy; or A is NHR³or N(R³)₂ wherein each R³ is independently selected from: H,(C₁₋₆)alkyl, (C₃₋₇)cycloalkyl, aryl and heteroaryl; R⁴ is (C₁₋₆)alkyl,(C₃₋₇)cycloalkyl, aryl, heteroaryl, (C₁₋₆)alkyl-aryl or(C₁₋₆)alkyl-heteroaryl, each of which being optionally substituted withone or more substituents independently selected from: (C₁₋₆)alkyl, halo,(C₁₋₆)haloalkyl, (C₁₋₆)alkylthio, amino, (C₁₋₆)alkylamino,di((C₁₋₆)alkyl)amino, aryl, heteroaryl, (C₁₋₆)alkyl-aryl,(C₁₋₆)alkyl-heteroaryl, and (C₁₋₆)alkoxy, wherein said (C₁₋₆)alkoxy isoptionally substituted with aryl or heteroaryl; or R⁴ is phenyl fusedwith a saturated or unsaturated 4- to 6-membered ring optionallycontaining one to three heteroatoms independently selected from N, O,and S; Z is O; Y is CH₂ or NH; B is selected from:

 wherein R⁵ is H, (C₁₋₆)alkyl, halo, (C₁₋₆)haloalkyl, (C₁₋₆)alkoxy,(C₁₋₆)alkylthio, (C₁₋₆)alkylamino, or di((C₁₋₆)alkyl)amino; X₂ is N orCR⁷; R⁶ and R⁷ are independently H, (C₁₋₆)alkyl, halo, (C₁₋₆)haloalkyl,(C₁₋₆)alkoxy, (C₁₋₆)alkylthio, (C₁₋₆)alkylamino, anddi((C₁₋₆)alkyl)amino, or, when X₂ is CR⁷, R⁶ and R⁷ are optionallybonded together to form a saturated or unsaturated 5- or 6-memberedring, optionally containing one or two heteroatoms independentlyselected from S, O and N; X₃ is O, S or NR⁸, wherein R¹¹ is H or(C₁₋₆)alkyl; and R^(c) is COOH, or SO₂NH₂; provided that, R⁵ and R⁶cannot both together be H and when R⁵ or R⁶ is H, then R¹ is not H. 12.The compound according to claim 1 wherein R¹ is (C₁₋₆)alkyl; X₁ is CH;R² is H; A is (C₃₋₇)cycloalkyl, phenyl, or a 5- or 6-membered monocyclicheterocycle, each of which being optionally substituted with one or moresubstituents independently selected from (C₁₋₆)alkyl, halo,(C₁₋₆)haloalkyl and aryloxy; or A is NHR³ or N(R³)₂ wherein each R³ isindependently selected from (C₁₋₆)alkyl, (C₃₋₇)cycloalkyl, aryl, andheteroaryl; R⁴ is aryl, or heteroaryl, both optionally substituted withone or more substituents independently selected from: (C₁₋₆)alkyl, halo,(C₁₋₆)haloalkyl, (C₁₋₆)alkylthio, amino, (C₁₋₆)alkylamino,di((C₁₋₆)alkyl)amino, aryl, heteroaryl, and (C₁₋₆)alkoxy, wherein said(C₁₋₆)alkoxy is optionally substituted with aryl or heteroaryl; or R⁴ isphenyl fused with a saturated or unsaturated 4- to 6-membered ringoptionally containing one or two heteroatoms independently selected fromN, O, and S; Z is O; Y is CH₂; B is:

 wherein R⁵ is (C₁₋₆)alkoxy; X₂ is CR⁷; R⁶ is (C₁₋₆)alkyl, halo or(C₁₋₆)haloalkyl, and R⁷ is H; or R⁶ and R⁷ are optionally bondedtogether to form a saturated or unsaturated 5- or 6-membered ring,optionally containing one or two heteroatoms independently selected fromS, O and N.
 13. The compound according to claim 1 wherein R¹ is H,methyl, or ethyl; both X₁ and X₂ are CH; each R² is independentlyselected from: H and halo; A is cyclohexyl, phenyl, 1-piperidyl,4-morpholinyl, N(H)cyclohexyl, or N(CH₃)cyclohexyl, said cyclohexyl,phenyl, 1-piperidyl and 4-morpholinyl being optionally mono- ordi-substituted with: (C₁₋₆)alkyl, halo, (C₁₋₆)haloalkyl, or aryloxy; R⁴is aryl, or heteroaryl, both optionally substituted with one or moresubstituents independently selected from: (C₁₋₆)alkyl, halo,(C₁₋₆)haloalkyl, (C₁₋₆)alkylthio, amino, (C₁₋₆)alkylamino,di((C₁₋₆)alkyl)amino, aryl, heteroaryl, and (C₁₋₆)alkoxy, wherein said(C₁₋₆)alkoxy is optionally substituted with aryl or heteroaryl; or R⁴ isphenyl fused with a saturated or unsaturated 4- to 6-membered ringoptionally containing one or two heteroatoms independently selected fromN, O, and S; Z is O; Y is CH₂ or NH; B is:

R⁵ is methoxy or ethoxy; R⁶ is halo; and R^(c) is COOH.
 14. The compoundaccording to claim 1 wherein R¹ is H or methyl; X₁ is CH; R² is H; A is4-morpholinyl, N(H)cyclohexyl, N(CH₃)cyclohexyl or 1-piperidinyl, said4-morpholinyl and 1-piperidinyl being optionally substituted with Me orphenoxy or optionally geminally difluorinated; R⁴ is thienyl, furanyl ornaphthyl optionally substituted with: methoxy or (C₁₋₆)alkyl, or R⁴ isphenyl optionally substituted with one to four of: methoxy, halo, orphenyl, or R⁴ is phenyl fused with a saturated or unsaturated 4- to6-membered ring optionally containing one to three heteroatomsindependently selected from N, O, and S; Z is O; Y is CH₂; B is:

R⁵ is methoxy; X₂ is CH; R⁶ is bromo; and R^(c) is COOH.
 15. Thecompound according to claim 1, or its enantiomers or diastereomersthereof, of the formula

wherein R¹, R², A, R⁴, Y, R⁵ and R⁶ are defined as in the table below;wherein with respect to R², the number indicates the position ofsubstitution on the phenyl ring: Cpd R¹ R² A R⁴ Y R⁵ R⁶ 101 Me H

Ph CH₂ OMe H 102 Me H

Ph CH₂ OMe H 103 Me H

Ph NH OMe H 104 Me H

CH₂ OMe H 105 Me H

Ph CH₂ OMe H 106 Me H

—(CH₂)₃—CH₃ CH₂ OMe Br 107 Me H

CH₂ OMe Br 108 Me H

CH₂ OMe Br 109 Me H

CH₂ OMe Br 110 H 1-F

CH₂ OMe Br 111 H H

CH₂ OMe Br 112 Me H

CH₂ OMe Br 113 Et H

CH₂ OMe Br 114 Me H

Me CH₂ OMe Br 115 Me H

iPr CH₂ OMe Br 116 Me H

CH₂ OMe Br 117 Me H

CH₂ OMe Br 118 Me H

CH₂ OMe Br 119 Me H

CH₂ OMe Br 120 Me H

CH₂ OMe Br 121 Me H

CH₂ OMe Br 122 Me H

CH₂ OMe Br 123 Me H

CH₂ OMe Br 124 Me H

CH₂ OMe Br 125 Me H

CH₂ OMe Br 126 Me H

CH₂ OMe Br 127

H

Me CH₂ OMe Br 128 Me H

CH₂ OEt H 129 Me H

Ph CH₂ OEt H


16. The compound according to claim 1, or its enantiomers ordiastereomers thereof the formula

wherein R⁴⁰, R⁴¹, R⁴², R⁴³, R⁴⁴, Y, and R⁶ are defined as in the tablebelow: Cpd R⁴⁰ R⁴¹ R⁴² R⁴³ R⁴⁴ Y R⁶ 201 H H H H H NH Cl 202 H H H H H NHBr 203 H H OMe H H CH₂ Br 204 H H H H OMe CH₂ Br 205 H H H H Me CH₂ Br206 H H Me H Me CH₂ Br 207 H H H OMe H CH₂ Br 208 H H H —CH₃ H CH₂ Br209 H H

H H CH₂ Br 210 H H SMe H H CH₂ Br 211 H H t-Bu H H CH₂ Br 212 H H CF₃ HH CH₂ Br 213 H H Cl H H CH₂ Br 214 H H

H H CH₂ Br 215 H H OMe H OMe CH₂ Br 216 OMe H OMe H OMe CH₂ Br 217 H H HH iPr CH₂ Br 218 H Me OMe H H CH₂ Br 219 H H H H H CH₂ Br 220 H F Ph H HCH₂ Br


17. The compound according to claim 1, or its enantiomers ordiastereomers thereof, of the formula

wherein R¹, A, R⁴, Y, R⁵, R⁶, X₂, and R^(C) are defined as in the tablebelow: Cpd R¹ A R⁴ Y R⁵ CR⁶—X₂ R^(c) 301 Me

CH₂ OMe CBr—CH SO_(2 NH) ₂ 302 Me

CH₂ H

COOH


18. The compound according to claim 1, or its enantiomers ordiastereomers thereof, of the formula (VI)

wherein R¹, A, R⁴, Z, Y, X₃, and R^(C) are defined as in the tablebelow: Cpd R¹ A R⁴ Y Z X₃ R^(c) 401 Me

NH S S COOH


19. A pharmaceutical composition comprising a therapeutically effectiveamount of a compound according to claim 1 in association with at leastone pharmaceutically acceptable carrier.
 20. The pharmaceuticalcomposition of claim 19 for use in the treatment or prevention ofpapillomavirus infection.
 21. The pharmaceutical composition accordingto claim 20 wherein the papillomavirus is human papillomavirus.
 22. Thepharmaceutical composition according to claim 21 wherein the humanpapillomavirus is low risk types 6 and
 11. 23. The pharmaceuticalcomposition according to claim 22 wherein the human papillomavirus istype
 11. 24. A method of treating or preventing a papilloma virusinfection in a mammal comprising administering to the mammal ananti-papilloma virus virally-effective amount of a compound according toclaim
 1. 25. The method according to claim 24 wherein the papillomavirusis human papillomavirus.
 26. The method according to claim 25 whereinthe human papillomavirus is low risk types 6 and
 11. 27. The methodaccording to claim 26 wherein the human papillomavirus is type
 11. 28.Use of a compound according to claim 1 to inhibit replication of apapillomavirus.
 29. A method of inhibiting replication of a papillomavirus comprising exposing the virus to an anti-papilloma virusvirally-effective amount of a compound according to claim
 1. 30. Use ofa compound according to claim 1 in the manufacture of a medicament forthe treatment or prevention of papillomavirus infection in a mammal. 31.The use according to claim 30 wherein the papillomavirus is humanpapillomavirus.
 32. The use according to claim 31 wherein the humanpapillomavirus is low risk types 6 and
 11. 33. The use according toclaim 32 wherein the human papillomavirus is type
 11. 34. An article ofmanufacture comprising packaging material contained within which is acomposition effective to inhibit a papilloma virus and the packagingmaterial comprises a label which indicates that the composition can beused to treat or prevent infection by a papilloma virus, wherein saidcomposition includes a compound according to claim
 1. 35. Apharmaceutical composition comprising an anti-papillomavirusvirally-effective amount of a compound of formula (II) or itsenantiomers or diastereoisomers thereof in association with at least onepharmaceutically acceptable carrier:

wherein R¹¹ is H, (C₁₋₆)alkyl, halo, (C₁₋₆)haloalkyl, (C₁₋₆)alkoxy,(C₁₋₆)alkylthio, amino, (C₁₋₆)alkylamino, di((C₁₋₆)alkyl)amino,(C₃₋₇)cycloalkyl, phenyl, or 5- or 6-membered heterocycle; X₄, X₅ and X₆are independently chosen from CR¹² and N, wherein each R¹² isindependently selected from: H, (C₁₋₆)alkyl, (C₁₋₆)alkoxy, halo,(C₁₋₆)alkylthio, (C₁₋₆)haloalkyl, amino, (C₁₋₆)alkylamino anddi((C₁₋₆)alkyl)amino; R¹³ is (C₁₋₆)alkyl, (C₃₋₇)cycloalkyl, aryl, orheterocycle, said (C₁₋₆)alkyl, (C₃₋₇)cycloalkyl, aryl and heterocyclebeing optionally substituted with R¹⁵ wherein R¹⁵ is H, (C₁₋₆)alkyl,(C₃₋₇)cycloalkyl, halo, (C₁₋₆)haloalkyl, (C₁₋₆)alkoxy, (C₁₋₆)alkylthio,amino, (C₁₋₆)alkylamino, or di((C₁₋₆)alkyl)amino, aryl, O-aryl, S-aryl,NH-aryl, (C₁₋₆)alkyl-aryl, heteroaryl, O-heteroaryl, S-heteroaryl,NH-heteroaryl or (C₁₋₆)alkyl-heteroaryl; or R¹³ is OR⁶, SR¹⁶, NHR¹⁶ orN(R⁶)₂ wherein R¹⁶ is independently selected in each instance from: H,(C₁₋₆)alkyl, (C₃₋₇)cycloalkyl, aryl and heteroaryl; and R¹⁴ is H,(C₁₋₆)alkyl, (C₃₋₇)cycloalkyl, aryl, heterocycle, (C₁₋₆)alkyl-aryl or(C₁₋₆)alkyl-heterocycle, wherein said (C₁₋₆)alkyl, (C₃₋₇)cycloalkyl,aryl, heterocycle, (C₁₋₆)alkyl-aryl or (C₁₋₆)alkyl-heterocycle areoptionally substituted with one or more substituents independentlyselected from: (C₁₋₆)alkyl, halo, (C₁₋₆)haloalkyl, (C₁₋₆)alkylthio,amino, (C₁₋₆)alkylamino, di((C₁₋₆)alkyl)amino, aryl, heteroaryl,(C₁₋₆)alkyl-aryl, (C₁₋₆)alkyl-heteroaryl, and (C₁₋₆)alkoxy, wherein said(C₁₋₆)alkoxy is optionally substituted with aryl or heteroaryl; or R¹⁴is phenyl fused with a saturated or unsaturated 4- to 6-membered ringoptionally containing one to four heteroatoms independently selectedfrom N, O, and S; or R¹⁴ is CH₂COOR¹⁷ or CH₂CONHR¹⁷, wherein R¹⁷ is(C₁₋₆)alkyl, (C₃₋₇)cycloalkyl, aryl or heterocycle, said (C₁₋₆)alkyl,(C₃₋₇)cycloalkyl, aryl and heterocycle being optionally furthersubstituted with: aryl or heteroaryl, both being optionally substitutedwith one to four R¹¹; W is NH or CH₂; Z is O or S; Y is CH₂, NH or 0; Tis aryl, or heteroaryl, said aryl and heteroaryl being optionallysubstituted with: one to three R¹¹, hydroxyl or sulfhydryl; and R¹⁸ isCOOH, COOR¹⁹, CONHR¹⁹, SO₂NHR¹⁹ or tetrazolyl; wherein R¹⁹ is H,(C₁₋₆)alkyl, (C₃₋₆)cycloalkyl or phenyl; or a pharmaceuticallyacceptable salt or ester thereof.
 36. The pharmaceutical compositionaccording to claim 35 wherein the papillomavirus is humanpapillomavirus.
 37. The pharmaceutical composition according to claim 36wherein the human papillomavirus is low risk types 6 and
 11. 38. Thepharmaceutical composition according to claim 37 wherein the humanpapillomavirus is type
 11. 39. Use of a compound of formula (II) or itsenantiomers or diastereoisomers thereof, including a pharmaceuticallyacceptable salt or ester thereof, in the manufacture of a medicament forthe treatment or prevention of a papilloma virus infection in a mammal,wherein the compound of formula (II) is defined as in claim
 35. 40. Theuse according to claim 39 wherein the papillomavirus is humanpapillomavirus.
 41. The use according to claim 40 wherein the humanpapillomavirus is low risk types 6 and
 11. 42. The use according toclaim 41 wherein the human papillomavirus is type
 11. 43. A method oftreating or preventing a papilloma virus infection in a mammalcomprising administering to the mammal an anti-papilloma virusvirally-effective amount of a compound of formula (II) or itsenantiomers or diastereoisomers thereof, including a pharmaceuticallyacceptable salt or ester thereof, or a composition according to claim35, wherein the compound of formula (II) is defined as in claim
 35. 44.The method according to claim 43 wherein the papillomavirus is humanpapillomavirus.
 45. The method according to claim 44 wherein the humanpapillomavirus is low risk types 6 and
 11. 46. The method according toclaim 45 wherein the human papillomavirus is type.
 11. 47. An article ofmanufacture comprising packaging material contained within which is acomposition effective to inhibit a papilloma virus and the packagingmaterial comprises a label which indicates that the composition can beused to treat or prevent infection by a papilloma virus, wherein saidcomposition includes a compound of formula (II) or its enantiomers ordiastereoisomers thereof, including a pharmaceutically acceptable saltor ester thereof, wherein the compound of formula (II) is defined as inclaim
 35. 48. A compound according to claim 1 to which at least one of adetectable label, an affinity tag or a photoreactive group is linked.